Общий замысел и основание нашего журнала «Клеточная Терапия и Трансплантация» (КТТ) базировались на долгосрочном сотрудничестве российских и европейских специалистов в области трансплантации костного мозга (ТКМ). Совместные исследования в смежных научных областях основывались на предыдущих контактах между российскими и европейскими гематологами, онкологами и экспертами в области молекулярной биологии и генной терапии с 1990-х гг. Ввиду тесных международных рабочих связей между врачами и программ подготовки молодых российских специалистов в зарубежных клиниках, проф. Борис В. Афанасьев, проф. Дж. Вагемакер, проф. Аксель Р. Цандер и другие известные специалисты признали необходимость специального международного издания для лучшего сотрудничества в данной области. Генеральная концепция журнала «Клеточная Терапия и Трансплантация» была разработана в ходе дискуссий на встречах в Вильседе и Европейской группы ТКМ в 2006-2008 гг.
Поэтому пилотный выпуск КТТ появился онлайн в июне 2008 г. с предисловием Михаила Горбачева, президента СССР, где были он выражал наилучшие пожелания журналу КТТ. На протяжении 2000-х годов М. С. Горбачев сделал большой вклад в развитие трансплантации костного мозга в России, профинансировал и обеспечил строительство НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, который открылся при Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в сентябре 2007 г. Таким образом, журнал КТТ явился существенной составной частью большой программы, направленной на развитие трансплантации гемопоэтических клеток в России и странах бывшего СССР и на обмен полезными данными с нашими западными коллегами. Публикации журнала КТТ предоставляли дополнительные ценные знания молодым специалистам из России, повышали их мотивацию и улучшали языковые навыки при написании их статей на английском языке. Статьи в КТТ также облегчали им защиту их диссертаций.
Со времени основания журнала КТТ, его общая издательская политика состояла в публикации компетентных мнений, а также современных клинических и научных результатов, полученных российскими и западными клиницистами и исследователями. Как ранее, так и в настоящее время мы принимаем статьи, написанные по-английски с расширенными российскими резюме, тем самым привлекая авторов и читателей, как из бывшего СССР, так и западных стран.
На протяжении этих лет мы гордились публикацией ряда исторических заметок об А. А. Максимове и А. Я. Фриденштейне и их инновационных идеях в гематологии, множеством аналитических обзоров о технологиях ТКМ, режимах терапии и новых лечебных препаратах, которые повышают терапевтическую эффективность и улучшают качество жизни пациентов, а также большим числом оригинальных статей. Каждый год КТТ публикует сводки презентаций и резюме докладов, представленных на ежегодном симпозиуме памяти Р. М. Горбачевой, посвященном трансплантации гемопоэтических клеток. Журнал КТТ реферируется в российских и западных базах данных (Scopus, ResearchGate, Google Scholar, E-library), а также находится в перечне изданий, где должны публиковаться статьи для соискателей кандидатской и докторской степеней признанных ВАК РФ.
Редакционный совет нашего журнала представлен широко известными специалистами по ТКМ и смежным вопросам из разных стран. Особая благодарность сле дует выразить проф. Акселю Р. Цандеру, проф. Герарду Вагемакеру и проф. Борису Фезе за их постоянное участие в нашей совместной работе и издательской деятельности журнала КТТ. Мы надеемся, что общая политика и содержание нашего журнала будут сохраняться, тем самым способствуя распространению научных сведений о трансплантации и повышению уровня знаний о клеточной терапии в российских и европейских клиниках, особенно о современных технологиях, включая генную терапию, для блага пациентов с онкогематологическими и наследственными заболеваниями.
The general idea and foundation of our Cellular Therapy and Transplantation Journal (CTT) were based on a long-term cooperation between Russian and European specialists in the area of bone marrow transplantation (BMT). Common studies in adjacent research topics stemmed from previous contacts between the Russian and European hematologists, oncologists, and experts in the fi eld of molecular biology and gene therapy since 1990s. In view of close working contacts between the clinicians from diff erent countries, and training programs for young Russian specialists in foreign clinics, a need for a special international edition for better cooperation was recognized by Prof. Boris V. Afanasyev, Prof. G. Wagemaker, Prof. Axel R. Zander and other prominent workers in the fi eld. The general concept of Cellular Therapy and Transplantation was elaborated during discussions at the Wilsede and EBMT Meetings in 2006-2008.
Therefore, the pilot CTT issue appeared online in June 2008, preceded by a foreword by Mr. Michael Gorbachev, the former Russian President who expressed his best wishes to the CTT Journal. Over 2000s Michael Gorbachev contributed much to development of BMT in Russia, by funding and construction of the R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation which was opened at the St. Petersburg State I. Pavlov Medical University in September 2007. Hence, the CTT Journal proved to be a suffi cient part of a big program aimed for development of hematopoietic transplantation in Russia and ex-USSR countries, and exchange of useful data with our Western colleagues. The CTT publications provided additional valuable knowledge for the young specialists from Russia, increased their motivation, and improved language skills when preparing their articles in English. The CTT articles also facilitated their Ph.D. defense.
Since launching the CTT Journal, its general editorial policy was to publish competent opinions, as well as modern clinical and research results obtained by Russian and Western clinicians and researchers. Then and now, we accept articles written in English language with extended Russian summaries, thus attracting authors and readership of both ex-USSR and Western countries.
Over these years, we have been proud of publishing some historical notes about A. A. Maximov, and A. Ya. Friedenstein and their innovative ideas in hematology, a number of comprehensive reviews on the BMT techniques, treatment regimens and novel curative drugs which increase therapeutic efficiency and improve quality of life in the patients, as well as a number of original articles. Every year, CTT publishes the abstracts of presentations and short reports from the R. Gorbacheva Memorial Symposium dedicated to hematopoietic stem cell transplantation. The CTT Journal is referred in Russian and Western databases (Scopus, Research-Gate, Google Scholar, E-library), being approved by the Russian State Commission for Academic Degrees and Titles.
Our Editorial Board is presented by the well-known specialists in BMT and related topics from diff erent countries. A special gratitude should be expressed to Professor Axel R. Zander, Prof. Gerard Wagemaker, and Prof. Boris Fehse for their long-range participation in our cooperation and the CTT editorial activities. We hope that the general policy and content of the Journal will retain, thus further promoting dissipation of transplantation science and improving knowledge in cell therapy in Russian and European clinics, especially, modern technologies, including gene therapy, for the sake of patients with oncohematological diseases and inherited disorders.
The general idea and foundation of our Cellular Therapy and Transplantation Journal (CTT) were based on a long-term cooperation between Russian and European specialists in the area of bone marrow transplantation (BMT). Common studies in adjacent research topics stemmed from previous contacts between the Russian and European hematologists, oncologists, and experts in the fi eld of molecular biology and gene therapy since 1990s. In view of close working contacts between the clinicians from diff erent countries, and training programs for young Russian specialists in foreign clinics, a need for a special international edition for better cooperation was recognized by Prof. Boris V. Afanasyev, Prof. G. Wagemaker, Prof. Axel R. Zander and other prominent workers in the fi eld. The general concept of Cellular Therapy and Transplantation was elaborated during discussions at the Wilsede and EBMT Meetings in 2006-2008.
Therefore, the pilot CTT issue appeared online in June 2008, preceded by a foreword by Mr. Michael Gorbachev, the former Russian President who expressed his best wishes to the CTT Journal. Over 2000s Michael Gorbachev contributed much to development of BMT in Russia, by funding and construction of the R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation which was opened at the St. Petersburg State I. Pavlov Medical University in September 2007. Hence, the CTT Journal proved to be a suffi cient part of a big program aimed for development of hematopoietic transplantation in Russia and ex-USSR countries, and exchange of useful data with our Western colleagues. The CTT publications provided additional valuable knowledge for the young specialists from Russia, increased their motivation, and improved language skills when preparing their articles in English. The CTT articles also facilitated their Ph.D. defense.
Since launching the CTT Journal, its general editorial policy was to publish competent opinions, as well as modern clinical and research results obtained by Russian and Western clinicians and researchers. Then and now, we accept articles written in English language with extended Russian summaries, thus attracting authors and readership of both ex-USSR and Western countries.
Over these years, we have been proud of publishing some historical notes about A. A. Maximov, and A. Ya. Friedenstein and their innovative ideas in hematology, a number of comprehensive reviews on the BMT techniques, treatment regimens and novel curative drugs which increase therapeutic efficiency and improve quality of life in the patients, as well as a number of original articles. Every year, CTT publishes the abstracts of presentations and short reports from the R. Gorbacheva Memorial Symposium dedicated to hematopoietic stem cell transplantation. The CTT Journal is referred in Russian and Western databases (Scopus, Research-Gate, Google Scholar, E-library), being approved by the Russian State Commission for Academic Degrees and Titles.
Our Editorial Board is presented by the well-known specialists in BMT and related topics from diff erent countries. A special gratitude should be expressed to Professor Axel R. Zander, Prof. Gerard Wagemaker, and Prof. Boris Fehse for their long-range participation in our cooperation and the CTT editorial activities. We hope that the general policy and content of the Journal will retain, thus further promoting dissipation of transplantation science and improving knowledge in cell therapy in Russian and European clinics, especially, modern technologies, including gene therapy, for the sake of patients with oncohematological diseases and inherited disorders.
The general idea and foundation of our Cellular Therapy and Transplantation Journal (CTT) were based on a long-term cooperation between Russian and European specialists in the area of bone marrow transplantation (BMT). Common studies in adjacent research topics stemmed from previous contacts between the Russian and European hematologists, oncologists, and experts in the fi eld of molecular biology and gene therapy since 1990s. In view of close working contacts between the clinicians from diff erent countries, and training programs for young Russian specialists in foreign clinics, a need for a special international edition for better cooperation was recognized by Prof. Boris V. Afanasyev, Prof. G. Wagemaker, Prof. Axel R. Zander and other prominent workers in the fi eld. The general concept of Cellular Therapy and Transplantation was elaborated during discussions at the Wilsede and EBMT Meetings in 2006-2008.
Therefore, the pilot CTT issue appeared online in June 2008, preceded by a foreword by Mr. Michael Gorbachev, the former Russian President who expressed his best wishes to the CTT Journal. Over 2000s Michael Gorbachev contributed much to development of BMT in Russia, by funding and construction of the R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation which was opened at the St. Petersburg State I. Pavlov Medical University in September 2007. Hence, the CTT Journal proved to be a suffi cient part of a big program aimed for development of hematopoietic transplantation in Russia and ex-USSR countries, and exchange of useful data with our Western colleagues. The CTT publications provided additional valuable knowledge for the young specialists from Russia, increased their motivation, and improved language skills when preparing their articles in English. The CTT articles also facilitated their Ph.D. defense.
Since launching the CTT Journal, its general editorial policy was to publish competent opinions, as well as modern clinical and research results obtained by Russian and Western clinicians and researchers. Then and now, we accept articles written in English language with extended Russian summaries, thus attracting authors and readership of both ex-USSR and Western countries.
Over these years, we have been proud of publishing some historical notes about A. A. Maximov, and A. Ya. Friedenstein and their innovative ideas in hematology, a number of comprehensive reviews on the BMT techniques, treatment regimens and novel curative drugs which increase therapeutic efficiency and improve quality of life in the patients, as well as a number of original articles. Every year, CTT publishes the abstracts of presentations and short reports from the R. Gorbacheva Memorial Symposium dedicated to hematopoietic stem cell transplantation. The CTT Journal is referred in Russian and Western databases (Scopus, Research-Gate, Google Scholar, E-library), being approved by the Russian State Commission for Academic Degrees and Titles.
Our Editorial Board is presented by the well-known specialists in BMT and related topics from diff erent countries. A special gratitude should be expressed to Professor Axel R. Zander, Prof. Gerard Wagemaker, and Prof. Boris Fehse for their long-range participation in our cooperation and the CTT editorial activities. We hope that the general policy and content of the Journal will retain, thus further promoting dissipation of transplantation science and improving knowledge in cell therapy in Russian and European clinics, especially, modern technologies, including gene therapy, for the sake of patients with oncohematological diseases and inherited disorders.
Общий замысел и основание нашего журнала «Клеточная Терапия и Трансплантация» (КТТ) базировались на долгосрочном сотрудничестве российских и европейских специалистов в области трансплантации костного мозга (ТКМ). Совместные исследования в смежных научных областях основывались на предыдущих контактах между российскими и европейскими гематологами, онкологами и экспертами в области молекулярной биологии и генной терапии с 1990-х гг. Ввиду тесных международных рабочих связей между врачами и программ подготовки молодых российских специалистов в зарубежных клиниках, проф. Борис В. Афанасьев, проф. Дж. Вагемакер, проф. Аксель Р. Цандер и другие известные специалисты признали необходимость специального международного издания для лучшего сотрудничества в данной области. Генеральная концепция журнала «Клеточная Терапия и Трансплантация» была разработана в ходе дискуссий на встречах в Вильседе и Европейской группы ТКМ в 2006-2008 гг.
Поэтому пилотный выпуск КТТ появился онлайн в июне 2008 г. с предисловием Михаила Горбачева, президента СССР, где были он выражал наилучшие пожелания журналу КТТ. На протяжении 2000-х годов М. С. Горбачев сделал большой вклад в развитие трансплантации костного мозга в России, профинансировал и обеспечил строительство НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, который открылся при Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в сентябре 2007 г. Таким образом, журнал КТТ явился существенной составной частью большой программы, направленной на развитие трансплантации гемопоэтических клеток в России и странах бывшего СССР и на обмен полезными данными с нашими западными коллегами. Публикации журнала КТТ предоставляли дополнительные ценные знания молодым специалистам из России, повышали их мотивацию и улучшали языковые навыки при написании их статей на английском языке. Статьи в КТТ также облегчали им защиту их диссертаций.
Со времени основания журнала КТТ, его общая издательская политика состояла в публикации компетентных мнений, а также современных клинических и научных результатов, полученных российскими и западными клиницистами и исследователями. Как ранее, так и в настоящее время мы принимаем статьи, написанные по-английски с расширенными российскими резюме, тем самым привлекая авторов и читателей, как из бывшего СССР, так и западных стран.
На протяжении этих лет мы гордились публикацией ряда исторических заметок об А. А. Максимове и А. Я. Фриденштейне и их инновационных идеях в гематологии, множеством аналитических обзоров о технологиях ТКМ, режимах терапии и новых лечебных препаратах, которые повышают терапевтическую эффективность и улучшают качество жизни пациентов, а также большим числом оригинальных статей. Каждый год КТТ публикует сводки презентаций и резюме докладов, представленных на ежегодном симпозиуме памяти Р. М. Горбачевой, посвященном трансплантации гемопоэтических клеток. Журнал КТТ реферируется в российских и западных базах данных (Scopus, ResearchGate, Google Scholar, E-library), а также находится в перечне изданий, где должны публиковаться статьи для соискателей кандидатской и докторской степеней признанных ВАК РФ.
Редакционный совет нашего журнала представлен широко известными специалистами по ТКМ и смежным вопросам из разных стран. Особая благодарность сле дует выразить проф. Акселю Р. Цандеру, проф. Герарду Вагемакеру и проф. Борису Фезе за их постоянное участие в нашей совместной работе и издательской деятельности журнала КТТ. Мы надеемся, что общая политика и содержание нашего журнала будут сохраняться, тем самым способствуя распространению научных сведений о трансплантации и повышению уровня знаний о клеточной терапии в российских и европейских клиниках, особенно о современных технологиях, включая генную терапию, для блага пациентов с онкогематологическими и наследственными заболеваниями.
Общий замысел и основание нашего журнала «Клеточная Терапия и Трансплантация» (КТТ) базировались на долгосрочном сотрудничестве российских и европейских специалистов в области трансплантации костного мозга (ТКМ). Совместные исследования в смежных научных областях основывались на предыдущих контактах между российскими и европейскими гематологами, онкологами и экспертами в области молекулярной биологии и генной терапии с 1990-х гг. Ввиду тесных международных рабочих связей между врачами и программ подготовки молодых российских специалистов в зарубежных клиниках, проф. Борис В. Афанасьев, проф. Дж. Вагемакер, проф. Аксель Р. Цандер и другие известные специалисты признали необходимость специального международного издания для лучшего сотрудничества в данной области. Генеральная концепция журнала «Клеточная Терапия и Трансплантация» была разработана в ходе дискуссий на встречах в Вильседе и Европейской группы ТКМ в 2006-2008 гг.
Поэтому пилотный выпуск КТТ появился онлайн в июне 2008 г. с предисловием Михаила Горбачева, президента СССР, где были он выражал наилучшие пожелания журналу КТТ. На протяжении 2000-х годов М. С. Горбачев сделал большой вклад в развитие трансплантации костного мозга в России, профинансировал и обеспечил строительство НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, который открылся при Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в сентябре 2007 г. Таким образом, журнал КТТ явился существенной составной частью большой программы, направленной на развитие трансплантации гемопоэтических клеток в России и странах бывшего СССР и на обмен полезными данными с нашими западными коллегами. Публикации журнала КТТ предоставляли дополнительные ценные знания молодым специалистам из России, повышали их мотивацию и улучшали языковые навыки при написании их статей на английском языке. Статьи в КТТ также облегчали им защиту их диссертаций.
Со времени основания журнала КТТ, его общая издательская политика состояла в публикации компетентных мнений, а также современных клинических и научных результатов, полученных российскими и западными клиницистами и исследователями. Как ранее, так и в настоящее время мы принимаем статьи, написанные по-английски с расширенными российскими резюме, тем самым привлекая авторов и читателей, как из бывшего СССР, так и западных стран.
На протяжении этих лет мы гордились публикацией ряда исторических заметок об А. А. Максимове и А. Я. Фриденштейне и их инновационных идеях в гематологии, множеством аналитических обзоров о технологиях ТКМ, режимах терапии и новых лечебных препаратах, которые повышают терапевтическую эффективность и улучшают качество жизни пациентов, а также большим числом оригинальных статей. Каждый год КТТ публикует сводки презентаций и резюме докладов, представленных на ежегодном симпозиуме памяти Р. М. Горбачевой, посвященном трансплантации гемопоэтических клеток. Журнал КТТ реферируется в российских и западных базах данных (Scopus, ResearchGate, Google Scholar, E-library), а также находится в перечне изданий, где должны публиковаться статьи для соискателей кандидатской и докторской степеней признанных ВАК РФ.
Редакционный совет нашего журнала представлен широко известными специалистами по ТКМ и смежным вопросам из разных стран. Особая благодарность сле дует выразить проф. Акселю Р. Цандеру, проф. Герарду Вагемакеру и проф. Борису Фезе за их постоянное участие в нашей совместной работе и издательской деятельности журнала КТТ. Мы надеемся, что общая политика и содержание нашего журнала будут сохраняться, тем самым способствуя распространению научных сведений о трансплантации и повышению уровня знаний о клеточной терапии в российских и европейских клиниках, особенно о современных технологиях, включая генную терапию, для блага пациентов с онкогематологическими и наследственными заболеваниями.
Introduction
Intensive cytostatic therapy is applied as a standard treatment in malignant disorders of hematopoiesis. E.g., antitumor chemotherapy of leukemias is performed in several steps: remission induction, consolidating and supportive therapy. In cases of high-risk relapse, the patient is subject to allogeneic hematopoietic stem cell transplantation (HSCT), in order to inactivate residual cancer cells. During last 30 years, allogeneic HSCT was used in more than a million of cancer patients. As fi rst step of treatment, they receive high-dose cytostatic therapy (conditioning treatment) which is usually combined with anti-infectious therapy. The conditioning therapy causes both acute cellular immune defi ciency which recovers within months and, even, years [1]. Moreover, severe damage of oral and intestinal epithelium develops after intensive cytostatic treatment, and massive antibacterial therapy lead to alterations of gut microfl ora composition [2]. Pathogenic bacteria and their products migrate to blood plasma and may cause septicemia with detection of microbes and viruses in blood and on mucosal surfaces.
Allogeneic transplantation is generally performed from HLA-compatible familial or unrelated donor and is oft en accompanied by autoaggressive graft -versus-host disease (GVHD), an infl ammatory epithelium lesion which also contributes to immune alterations and intestinal dysfunction. Such triple eff ect of cytotoxic drugs, allogeneic immune interactions, and immune defi ciency should also change intestinal microbiota and its feedback eff ects upon host organism, including severe autoaggressive reactions [3].
The aim of our review is to specify biological and treatment- related factors causing changes of gut microbiota in the course of intensive cytostatic therapy and to delineate potential approaches to normalization for intestinal microbiome in such patients.
Previous experience with germ-free mice
The story began 50 years ago, when “gnotobiotic” (germfree) mice showed longer survival aft er irradiation at gut-damaging doses, compared to animals with normal gut microflora [4]. In a later study, the dogs subjected to lethal irradiation and bone marrow transplantation treated with antibacterial drugs proved to alleviate posttransplant complications aft er gut decontamination [5]. In 1980’s, total or selective gut decontamination (e.g., neomycin, polymyxin B amphotericin B) to prevent posttransplant infections (and maintain colonization resistance) was implemented into routine practice of hematopoietic stem cell transplantation [6]. Modern schedules for gut decontamination in cytopenic and immunocompromised patients include diff erent antibacterial, antifungal and antiviral drugs [7]. Prophylactic monotherapy with levofl oxacin also seems to decrease rates of infection aft er intensive chemotherapy in cancer [8]. Fluoroquinolone-containing schedules and other conventional gut decontamination protocols seem to be suboptimal under current epidemiological environment [9]. Th ese approaches should be directed for sparing necessary microbial diversity in gut microbiota and minimize risk for antibiotic-resistant infections.
“Normal” and changed human gut microbiota
Intestinal microbiota consists of myriads microorganisms, comprising a dynamic biological system functioning within a host organism. Human gut microbiota includes >1000 known microbial and fungal species [10]. Gut virome also contains hundreds viral species, both, phages and vertebrate viruses [11]. Over last years, possible role of the microbiota variety is described in a series of extensive review articles [12]. Generally, the major massive of intestinal microbiota may be classifi ed into several big classes: anaerobic Clostridia and mostly aerobic Bacteroides, Proteobacteria. Anaerobic clostridial species seem to perform a big deal of metabolic events in normal state, producing some essential metabolites for the host organism, e.g. short-chain fatty acids necessary for enterocyte survival and regulating immune eff ects in the host. Common changes in main classes of microbiota are associated with diff erent gastrointestinal disorders, e.g., infl ammatory bowel diseases [13].
Enteric permeability, microbial translocation and effector molecules
Viable intestinal microbiota produces big amounts of biologically active compounds which may under certain conditions penetrate from intestinal lumen via enteric wall to blood and lymph vessels. Live intestinal bacteria are thought to cross enteric/blood barrier in cases of intestinal damage caused, e.g., by intensive cytostatic treatment, or in severe immune defi ciency as it is seen in AIDS patients being a sign of the so-called bacterial translocation [14]. Bacterial components and metabolites in blood serum are known clinical markers of the patients with septicemia [15]. E.g., lipid A (lipopolysaccharide, LPS) is a component of endotoxin from Gram-negative bacteria, being detectable in blood plasma or urine. Th e LPS presence in serum suggests blood contamination with these bacteria or their fragments. Other plasma markers of septicemia are produced by the host cells (soluble CD14; LPS-binding protein etc.). LPS in clinical material is detected by in vitro test with Limulus lysate, whereas lipid A may be found and quantifi ed by means of ELISA or mass-spectrometry.
Th e 2,3-indoxyl sulfate (IS) is a useful marker of a gut dysbiosis, being produced by gut bacteria from tryptophan [16]. It is determined quantitively in blood plasma or urine by means of high-performance liquid chromatography/mass spectrometry. High IS amounts in blood are found in severe infections, intestinal dysbiosis, leakage of intestinal or hepatic barriers. Increase in other microbial metabolites, p-cresyl sulfate and trimethylamine-N-oxide is of similar diagnostic signifi cance. By the contrary, decreased blood citrulline may be a sign of intestinal damage, since it is synthesized by enterocytes [17].
Microbiota and immune response: APC and Th17 T cell network
Microbial and viral antigens, while penetrating mucosae, regional microvessels and lymph nodes, elicit local and regional polyclonal B- and T cell-mediated immune responses, thus being a key factor of normal maturation and functioning of immune system. Important role of intestinal microfl o ra in development and tuning of general immune response in humans, especially, in childhood, is extensively discussed in a number of review articles [18].
Th e mechanisms of immune maturation proceed via Th 17 and a chain of other signaling factors. Composition of gut microbiota and HLA antigens in host organism are also mutually dependent, both in normal and diseased persons, at least, in children, upon education of their immune system [19].
Hence, there are bidirectional relations between intestinal microbiota and the host immune system which may sufficiently modify the gut microbiome, along with immediate eff ects of cytostatic therapy, as well as long-term clinical outcomes, especially during hematopoietic stem cell transplantation (HSCT), due to minor diff erences in HLA antigens between donor and recipient.
Individual diversity of gut microbiota with age and dietary factors
During pregnancy, fetal intestine is sterile, being influenced by a number of external and internal factors [20, 21]. Th e extrinsic factors are – geographic area, maternal and surrounding environment bacteria, the way of childbirth – natural or by caesarean section, hygiene measures, feeding habits, drug therapies. As usual, colonizing bacteria derive from the mother – mainly vaginal and intestinal microbiota, breast milk and surrounding environment [22].
Th e intrinsic factors include neonatal genetics, bacterial mucosal receptors and interactions, intestinal pH and secretions, and immune response [24, 25].
One of the most important factors during the first months of life aff ecting the qualitative and quantitative composition of the microbiota is the fact of breast-feeding, which in addition to the energy function, provides immunoregulation [26], the digestive system functioning due to the presence of growth factors, cytokines, immunoglobulins and digestive enzymes in its composition [27].
During the fi rst and second year of life, diff erences between breast- and formula-fed infants are lost [28]. But short- and long-term eff ects of breast-feeding are much better in comparison to formula-fed infants reducing the incidence of allergic and autoimmune diseases [29], infl ammatory bowel diseases, cardiovascular diseases, obesity, type-2 diabetes [30, 31].
In the future, microbiota composition changes and its functional activity depend on nutrition features [32]. For example, the commitment to a Western diet, which typically consist of red meat, animal fat, high sugar and low fi ber food, leads to an increased number of Bacteroides phyla (mainly mucin-degradating bacteria) and Ruminococcus [33], reduced number of obligate bacteria, especially in the elderly [34]. While diet rich in fi ber correlate with larger bacterial diversity [35] and provide more functional microbiota activity, the degree of immunoregulation and cancer prevention [36].
One of the important questions is the impact of probiotics in the setting of availability to change microbiota characteristics and functioning is still controversial and depends on diagnosis and initial bacteria profi le. Probiotics are defined as «live microbial food supplements or components of bacteria which have been shown to have benefi cial eff ects on human health» and generally contain bacteria belonging to the genera Lactobacillus and Bifi dobacterium. It is shown that probiotics may have positive infl uence on immune functions, blood cholesterol decrease, vitamin synthesis, anti-cancerogenesis and anti-bacterial eff ect [37]. On the other hand, there is data indicating that probiotics are unable to colonize intestine for a long period of time, and have less efficacy in treatment of antibiotic associated diarrhea [38].
Some specific host-microbiota relations were found by a joint team from Netherlands and Russia who performed metagenomic sequencing in 1,514 subjects [39]. Using GWAS approach, they have found signifi cant associations of 9 human genome loci with microbial taxonomies and 33 loci with microbial pathways, including genome-wide signifi cance for the C-type lectin molecules CLEC4F-CD207 at 2p13.3 and CLEC4A-FAM90A1 at 12p13, and association of a functional LCT SNP with the Bifi dobacterium genus (P=3.45×10-8). These findings suggest an evidence of a gene-diet interaction for the regulation of gut Bifi dobacterium population.
However, an extensive genotype and microbiome study from the same workers based on the samples from 1,046 healthy individuals of diff erent ancestry who shared a relatively common environment has shown that the host genetics does not suffi ciently contribute to the microbiome composition [40]. Important similarities are found in the microbiota composition from genetically unrelated individuals who have common household. An estimated value of >20% of the inter- person microbiome variability is shown to be associated with dietary factors, drugs and individual anthropometry. Indeed, despite suffi cient eff ects of some gene variants, an impact of non-heritable factors, such as diet, seems to predominate the effects of host genetic background [41].
Figure 1. Overview of age-dependent human gut microbiota colonization (Note enrichment with anaerobic Firmicutes with high-fat and protein diet). Diversity of the gut microbiota increases with age until it becomes a stable adult microbiota. (Tanaka, Nakayama, 2017)
Figure 2. Microbial composition at the phylum level based on 16S rRNA gene sequences. BF = Before treatment; AF = After treatment; ATB = Antibiotics. For all antibiotics N= 21; for b-lactams N = 11; for fluoroquinolones N= 10 (Panda et al., 2017)
Microbiota affection by antimicrobial and anticancer therapy
Intensive cytostatic therapy is universally accompanied by leucopenia an temporary cellular immune defi ciency, thus causing activation of many opportunistic infections [42]. E.g., the Clostridium diffi cile infection is considered an important factor of intestinal disorders and general immune suppression in childhood [43]. Th e antibiotic-resistant bacterial strains occur at higher rate in gut, as seen from results of routine bacteriological studies.
Over last years, numerous studies show depletion of distinct bacterial groups as shown by next-generation sequencing. Load and composition of fecal microbiota were studied immediately aft er treatment in 21 patients, who received broad-spectrum antibiotics such as fl uoroquinolones and b-lactams [44]. Fecal samples were collected from all participants before treatment and one week aft er for microbial load and community composition analyses by quantitative PCR and pyrosequencing of the 16S rRNA gene. Th e study has shown a decrease in total bacterial load, and ratio of sufficient anaerobic bacteria. At the phylum level, the treatment with antibiotics increased the Bacteroidetes/Firmicutes ratio, as well as at the genera levels, mostly, due to Lachnospiraceae and Blautia exhaustion.
By contrary, experimental treatment of mice with cyclophosphamide is associated with depletion of Bacteroidetes in gut microbiota, along with accumulation of potentially harmful bacteria [45].
However, the question remains open, how combined antibacterial/anticancer therapy (e.g., cyclophosphamide) will aff ect intestinal microbiota in patients with malignancies and aff ect clinical outcomes. To this purpose, future clinical studies are required. Disturbed composition of gut microfl ora may be accompanied by remarkable functional changes of both anti-infectious and antitumor immunity [46].
Gut microbiota and acute GvHD
Acute GvHD is a common and oft en life-threatening HSCT complication caused by cytotoxic effects of donor T cells against skin and gut epithelium of the patients. GvHD severity may vary from grade 1 (mild reaction) to III-IV. A lot of genetic factors are shown to predispose for severe GvHD. Moreover, some infectious factors seem to cause or modify clinical course of GvHD, such as reactivation of CMV or EBV [1, 42].
Possible role of gut bacteria as a risk factor for GvHD is now questioned. E.g., antibacterial and cytostatic therapy before HSCT causes depletion of Clostridiales order, especially, Blautia genus. Reduction in these clostridiococci proved to be associated with higher GvHD mortality in these patients [47]. Diff erent changes of gut microbiota and relevant immune mechanisms promoting GvHD in allo-HSCT patients were recently summarized [48, 49].
Host pleiotropic genes: their presumable effects upon gut microbiota
Aft er initial optimism on predisposing role of functional gene variants in various disorders, some cautions appeared, when interpreting possible changes in genetic immune regulation, e.g., aft er hematopoietic stem cell transplantation. Th e problem is that, besides numerous gene polymorphisms of protein-encoding segments, one should consider effects of other single-nucleotide polymorphisms (SNPs) in regulatory elements and small molecules, like as microRNAs (miRNAs), and their interactions. Hence, phenotypic eff ects for most SNPs may be rather blurried and not reproducible when studied in diff erent populations and clinical series, as reviewed by Gam et al. [50].
About 100 genes or allelic variants, mostly those controlling immune functions of Th 1, Th 2, and Th 17 eff ector populations, were shown to be associated with susceptibility with infl ammatory bowel diseases (IBD), as reviewed by Basso et al. [51].
However, at the present time, current GWAS studies allowed to fi nd correlations between genotype and phenotype for a number of pleiotropic human genes which modify quite diff erent disorders, e.g., lipid disturbances and immune diseases [52]. A detailed genotype-phenotype analysis has revealed shared eff ects common for gut immune disorders (e.g., Crohn's disease, ulcerative colitis, celiac disease etc.), and lipid biology. Th ese genes concern several shared pathways including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1).
ATG16L1 and gut pathology
The ATG16L1 gene encodes an autophagy protein which is produced in many cell types, including antigen-presenting cells. Among diff erent polymorphisms, a single variant of ATG16L1 (rs2241880, T300A) may predispose for development of Crohn’s disease. Th e protective ATG16L1 allele encodes threonine at amino acid position 300 (ATG16L1*300T), whereas ATG16L1*300A encoding alanine confers higher risk for development of Crohn’s disease [53]. In human intestinal epithelium, the Crohn’s disease-associated ATG16L1 coding variant shows impaired capture of internalized Salmonella within autophagosomes. Th us, we propose that the association of ATG16L1*300A with increased risk of Crohn’s disease is due to impaired interactions with bacterial and decreased bacterial capture by autophagy.
ATG16L1 in the intestinal epithelium was shown to prevent loss of Paneth cells and exaggerated cell death in animal models of experimental infl ammatory bowel disease, and, interestingly, allogeneic hematopoietic stem cell transplantation. The mutant Atg16L1HM mice are more aff ected by graft -versus-host disease (GVHD) aft er allo-HSCT. Hence, ATG16L1 seems to keep the intestinal barrier by inhibiting epithelial cell death [54].
An elegant study was performed by Sadabad et al. [55]. The infl amed and non-infl amed sites of ileal mucosa from ATG16L1- typed patients with Crohn’s disease were studied, with respect to microbiota composition at these sites. Infl amed ileal tissue of patients homozygous for the ATG16L1 protective allele showed decreased numbers of Bacteroidaceae and Enterobacteriaceae and increased Lachnospiraceae. Upon in vitro assays, the monocytes homozygous for the ATG16L1 risk allele showed impaired killing of pathogenic E.coli under infl ammatory conditions. However, the ATG16L1 allele did not aff ect the bacterial composition in the non-infl amed ileal tissue. Th e authors suggest that the host cellular immunity seems to regulate the gut microbiota composition by genetic mechanisms.
Another study [56] has shown that the common GG variant of ATG16L1 interfered with the production of IL-1β, which was highly induced in PBMCs from patients with GG genotype by exposure to pathogenic E.coli. Th e authors have also observed that the T300A variant in patients with CD strongly increases the risk for complicated fi stulizing disease, and signifi cantly aff ects antibacterial responses in vitro. Meanwhile, any studies on the role of ATG16L1 in HSCT are absent in available literature
PD-1 gene
The PD-1 and its ligands (PD-1L) represent a system of costimulatory signal proteins that regulate activation and deactivation of T cells, modulates immune response to infectious pathogens and tissue antigens, thus mediating some autoimmune conditions [57]. PD-1 is encoded by the PDCD1 gene, being expressed on many cell types in humans. Hence, its expression may sufficiently influence both antiinfectious and antitumor response in HSCT patients.
PD-1 is a coinhibitory receptor that is inducibly expressed on T cells and B cells, natural killer T cells, and monocytes. Carriers of the A allele express lower levels of PD-1 receptor on the Treg cells (CD4+CD25+ cells) [58]. Th e variable G/A site is located in an intronic enhancer (intron 4, position 7,146) within a DNA-binding site for the RUNX1 transcription factor. Appropriate gene variant was called PD-1.3 (rs11568821). Th e common variant allele A is suggested to contribute to an aberrant transcriptional regulation of PD-1 in SLE and other autoimmune diseases.
However, typing of the PDCD1 gene may be also informative in transplantation settings. I.e., Hoff mann et al. [59] have genotyped the PD-1 variants in 469 seropositive kidney graft recipients and showed a signifi cant correlation between CMV reactivation and PD-1.3 allele A which proved to be associated with CMV infection posttransplant. Interestingly, inclusion of functional IL12B 3’UTR variants increased this association. In other study, the PD-1.3 variant was typed in 1119 kidney recipients and 181 lung recipients [60]. In 481 kidney transplants, the A allele carriers showed less common kidney graft failure than the G homozygotes. Moreover, evaluation of 85 lung recipients has shown similar results, i.e., the A-carriers had longer survival, and better function of transplanted organ. In addition, the, AA recipients had a stronger anti-CMVpp65 T-cell response than the GG-typed patients.
Effects of donor PD-1 variants upon clinical course of post-HSVCT period were presented by Santos et al. [61]. The workers have found an increased risk of grades II to IV graft -versus-host disease (GvHD) when the grafts were used from the donors homozygous for the A allele of the rs11568821 SNP. Th ose subjects comprised only 30 cases out of 1500 (ca.1.5%). Meanwhile, the PD-1.3 G>A genotype of the donor was not associated with overall survival or relapse incidence. Hence, the PD-1 gene polymorphism eff ects seemed to aff ect, mainly the GVHD immune aspect in this extensive study.
Association between PD-1 variants and sepsis outcomes was also found by Mansur et al. [62] who studied the rs11568821 SNP in 219 patients with severe sepsis. Th e 3-month mortality proved to be much higher for the GG group than for A allele carriers, with increased scores of multiple organ failure.
A number of novel inhibitors of PD-1 or PD-1 ligand are now introduced into clinical practice. In this respect, certain probiotic gut bacteria are considered a suffi cient modifying factor when treating malignancies with these immune
checkpoint inhibitory drugs [63].
FUT2 gene
Th is gene encodes fucosyl transferase, an enzyme adding a fucose residue, thus producing secretor state of H blood group antigen. Th is surface molecule also serves as a receptor for some intestinal viruses, thus the secretor state of FUT2 largely determines susceptibility to rotavirus and some other gut viral infections [64].
Additional evidence for the FUT2 gene polymorphism as a factor of rotavirus infection was found in the study by Günaydın et al. [65]. Rotavirus-specifi c antibody titers proved to be signifi cantly higher in persons with secretor FUT2 variants than in non-secretors.
A special meta-analysis (about 10,000 cases) as revealed a strong association between the rs601338 (W154X) in the FUT2 gene [66]. Th e children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhea, presumably, due to decreased numbers of cell receptors for pathogenic viruses (e.g., rotavirus).
To characterize metabolic eff ects of FUT2 gene polymorphism upon the mucosal ecosystem, a simultaneous assessment of microbiome, meta-proteome and meta-metabolome was performed in 75 endoscopic lavage samples from the cecum and sigmoid from 39 healthy subjects with diff erent FUT2 gene status (rs601338 G>A). Th e general metagenomic analysis revealed perturbations of energy metabolism in the microbiome from the non-secretor persons, i.e., enhanced carbohydrate and lipid metabolism, altered glycan biosynthesis and depleted amino-acid metabolism. Similar changes were reproduced in mice carrying the FUT2(-) genotype [67].
However, the associations between FUT2 secretor genotype and gut microbiota diversity were not confi rmed by a recent study performed in 1190 healthy persons since no correlations were revealed for alpha-diversity, or microbial composition assessed by NGS approach [68].
Other human genes potentially changing gut microbiota
Several years ago, the group by Holler et al. [69] has discovered a distinct correlation between certain polymorphisms of TLR and NOD2/CARD gene and high incidence of acute intestinal GVHD aft er HSCT. Th ese genes encode specifi c pattern-recognition receptors for bacterial antigens and mediate acute infl ammation switched by innate mechanisms. Special studies of intestinal biopsies from the GVHD patients
have shown loss of protective CD4 T cells which was more pronounced in carriers of NOD2/CARD15 gene variants [70].
Relations of NOD/CARD system and other gut disorders is also confi rmed by the results of Hrnčířová et al. [71] concerning distinct associations between Crohn's disease and some gene variants of CARD15/NOD2 gene.
Associations between NOD/CARD polymorphisms and posttransplant infections were studied by Grube et al. [72]. Th e authors found a signifi cant association between the presence of donor NOD2 SNP13 (3016_3017insC) and the incidence of septic shock (P <002). In multivariate analysis, donor NOD2 SNP13 appeared as an independent risk factor for the incidence of septic shock aft er allo-SCT.
In a Chinese study of sepsis cohort, the authors did not found any signifi cant associations for either TLR gene polymorphisms (rs4986790 or rs4986791) with sepsis susceptibility in total analysis in any genetic models [73].
Less significant (minor) diff erences for other gene variants may be obtained in large study groups, found due to big statistics.E.g., an international group has tested 10,523 IBD cases and 5,726 non-IBD controls by means of GWAS approach using the Illumina technique [74]. Th e workers have revealed a highly signifi cant association between between Crohn’s disease and a missense variant in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 Ala391Th r, rs13107325). Th e association of this SNP with microbiota was assessed in 338 colonic mucosal lavage samples using 16S rRNA sequencing. Th e Crohn’s disease risk allele proved to be associated with altered colonic mucosal microbiome in healthy controls and the patients (p=0.0009). Among major bacterial taxa of colon microbiota, the SLC39A8 Th r391 allele carriers exhibited signifi cant depletion of, e.g., Coprococcus, Roseburia, Lachnobacteria, Faecalibacterium prausnitzii and Ruminococcus gnavus in Crohn’s disease patients.
Pro- and anti-cancer effects associated with altered composition of intestinal microbiota
Over last years, abnormal intestinal microbiota is recognized as a factor of cancer treatment effi ciency and, especially, in cancer immunotherapy [75]. Potential associations between altered gut microbiota and clinical outcomes of malignancies are studied
E.g., colonic presence of Fusobacterium nucleatum correlates with increased risk for colorectal cancer, and its overpresentation in stool is shown to be associated with higher resistance of this tumor to chemotherapy [76].
In murine experiments, it was shown that prevalence of some intestinal Gram-positive bacteria may increase effi ciency of cytostatic tumor treatment, and, vice versa, antibacterial therapy eliminating Gram(+) microbes caused a decreased response of the tumors to cyclophosphamide treatment [77]. Th e authors suggest this biological eff ect to be mediated by the Th 17 T cell network which is switched by gut microfl ora-derived antigens. Appropriate clinical study was performed in patients with chronic lymphocytic leukemia (CLL) receiving cytostatic therapy [78]. A subgroup of patients treated with antibiotics against Gram-positive bacteria showed earlier progression of malignancy and decreased long-term survival.
Vice versa, predomination of a bacterial population represented mostly of Eubacterium limosum correlated with decreased risk of relapse/progression posttransplant [79]. Eubacterium limosum belongs to anaerobic bacteria producing butyric and other short-chain fatty acids which are considered to support viability and functioning of gut epithelium and local immune response [80].
Moreover, many attempts were made to correct or replace the damaged gut microbiota with specifi c strains of Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, or other probiotics [81], causing partial clinical responses in the patients with immune disorders. Probable potentiation of immune checkpoint inhibitory (anti-PD-1) therapy will be achieved, using distinct probiotic gut bacteria [63].
Probiotics and fecal transplantation post-HSCT
Fecal transplantation as a tool for microbiota substitution was proposed centuries ago. However, clinical indications for FMT and microbial markers of FMT effi ciency were developed within last 2-5 years. Th ese indications are based on the integral assessment of gut microbial spectrum performed by diff erent NGS techniques allowing to and assess ratio between distinct bacterial classes and genera [82].
Fecal microbiota transplantation (FMT) is now proposed as a substitution correcting therapy in the disorders characterized by shift s in microbial species, or other disturbances of the gut microbiota (Crohn’s disease, nonspecifi c ulcerous colitis, persistent C.diffi cile infections). Over recent years, sporadic small studies of FMT aft er hematopoietic SCT were performed in several patients with steroid-resistant intestinal GVHD by the groups from Japan and Netherlands, showing safety and satisfactory clinical effi ciency of the treatment method [83, 84]. At our BMT clinics, we have performed small studies with 11 patients who underwent allogeneic HSCT and suff ered with multiresistant microbial infections [85]. In most of the patients treated by FMT, fast clinical response was observed, along with positive dynamics of microbial fl ora in their stool samples. Our further studies are aiming to extend indications for FMT usage aft er allo-HSCT, in order to treat bacterial complications and immune disturbances (i.e., graft -versus-host disease) which suffi ciently depends on gut microbiota changes [86].
Appropriate clinical trials on the fecal microbiota transplants (FMT) have been carried out since 2014, according to the Clinical trials.gov registry, mostly, in Crohn’s disease, non-specifi c ulcerous colitis, resistant C.diffi cile infection. A total of 46 FMT trials for various clinical indications are registered in this fi eld, mostly for the phase I (safety and tolerance).
Gut virome in normal state and after HSCT
Bacteriophages
Only limited number of works concerns gut virome as a big variety of bacteriophages and eukaryotic viruses living in human cells. A competent review by Columpsi et al. [87] highlighted the issue of the intestinal bacteria and phage equilibrium, probability of eubiosis shift s, due to the phage lytic eff ects, thus causing health disorders. Moreover, the products of bacterial lysis and viral antigens could potentially trigger some adverse infl ammatory modulations. Th ere is a large heterogeneity of phages, which are infecting, mostly, specifi c bacterial classes and are difficult for appropriate taxonomic classifi cation. Ongoing epidemiological studies of intestinal phages are mostly performed by the NGS method, i.e., parallel sequencing of multiple small fragments of DNA followed by in silico alignment and reconstruction of multiple genomes, in order to identify known and novel phage
sequences.
A recently described intestinal crassPhage with in silico estimated properties, however, with unknown incidence and epidemiological features was described several years by means of modern NGS technique and in silico digital characterization of this, previously unknown phage which is probably living in Bacteroides and is detectable in ca. 73-77% of humans , is able to vertical transmission [88]. Moreover, the authors have shown its transmission to the recipient during fecal microbiota transplantation in C.difficile infection, thus showing an opportunity of tracing its migration pathways.
Eukaryotic cell viruses
Generally, a number of RNA and DNA viruses living in eukaryotic intestinal cells are detected in normal human gut, including rotavirus, astrovirus, calicivirus, norovirus, hepatitis E, adenoviruses etc. [87]. Moreover, quite recently, multiple “novel” RNA and DNA viruses were identifi ed in gut microbiota by their specifi c gene sequences, e.g., Picornaviridae, Coronaviridae, Astroviridae, Parvoviridae members, using high-coverage NGS approach [89].
Clinical viral infections and reactivation of diff erent intestinal viruses were extensively studied in hematopoietic stem cell and organ transplantation, including adenovirus, bocavirus, coronavirus, human herpesvirus-6, lymphocytic choriomeningitis virus, measles, mumps, metapneumovirus, parainfl uenza, rotavirus, etc. [90].
Routine clinical protocols for hematopoietic stem cell transplantation include weekly or bi-weekly multiple PCR screening for herpesviruses (cytomegalovirus, Herpes simplex, Epstein-Barr virus) and, especially, adenovirus for the
fi rst 1-2 months posttransplant which correlate with diff erent life-threatening complications [91]. Virus persistence in blood or stool may require further monitoring of viral load and consider the role of pathogen in intestinal disorders (i.e., prolonged diarrhea, intestinal GVHD). A suffi cient role of altered gut virome in HSCT was shown by Legoff et al. [48]. Th e authors have undertaken a global NGS study of gut microbiota in HSCT patients over diff erent time points and have found increased proportion of picobirnavirus (PBV) sequences in stool of the patients who later developed acute enteric GVHD. Th e increased PBV levels were revealed both before and up to 1 month posttransplant.
Interestingly, filterable (potentially, viral) substances of gut microbiota may be also eff ective in fecal transplantation. A German group [92] has used stool samples passed through Seitz fi lters, thus removing all native microbes, leaving presumably viral particles and some bacterial components. Th ese fl uid preparations were delivered to intestines of the patients with C.diffi cile infection and have produced good clinical eff ect, despite absence of intact bacteria in the fecal transplant. Eff ect of such treatment, if it will be reproduced, may be dependent on bacteriophages and human viruses present in the cell-free fl uid used by the workers. Potential role of bacteriophages in posttransplant conditions is suggested in the review article by Górski et al. [93]. Th is paper contains a collection of data on positive immune-mediated eff ects of intestinal bacteriophages upon intestinal epithelial cells, thus, probably, causing mitigation of graft - versus-host disease in humans. Worthy of note, a special study with FMT in C.diffi cile infection has shown that the donor-derived bacteriophages (specifi cally, Caudovirales) were expanded to larger degree in the patients responding to FMT than in those who did not [94]. Vice versa, the FMT recipients who received donor faeces with higher Caudovirales abundance were successfully treated with FMT. Appropriate studies in HSCT setting would be of suffi cient value in future, thus evaluating role of the phage component on FMT effects.
Future prospects
Despite good current knowledge on sufficient role of intestinal microbiota in HSCT setting, some issues remain unresolved.
First of all, most studies on positive effects of microbiota were performed in experimental models, thus requiring specifi c evaluation of these facts in human patients. Secondly, when dealing with complex bacterial network of microbiota in clinical settings, we still do not know what exact microbial species (or classes) are producing eff ector molecules modifying human immune response leading to severe GvHD or associated antitumor eff ects of immune therapy. To compare them with healthy subjects, the normal ranges should be established for distinct classes of intestinal microbiota within diff erent age groups. Th irdly, the qualitative and quantitative ranges of normal intestinal microbiota should be specified by classical bacteriological and immunological diagnostics accomplished with multiplex DNA diagnostics (multiplex PCR and next-generation sequencing) of stool samples from healthy persons. As a result, the new molecular targets could be suggested for improved immune therapy of oncological diseases, especially, in childhood. A special issue bears on proven combined eff ects of the antibacterial/anticancer therapy (e.g., cyclophosphamide) upon intestinal microbiota, with appropriate consequences for early HSCT complications and risk of relapses in human leukemias, lymphomas and some pediatric malignancies.
Due to absence of notable clinical recovery in HSCT from the probiotics treatment, one may, at this step of clinical research, propose a full-microbiota replacement for treatment of severe intestinal dysbioses, i.e., introduction of normal mixed donor microbiota to the gastrointestinal tract, aiming for rapid recovery of normal microbial composition. Such experimental treatment option is a kind of biotherapy which is now eff ectively used in the patients with persistent C.diffi cile infection, intestinal bowel diseases etc. Hence, fecal microbiota transplantation is feasible in HSCT patients, fi rst of all in antibiotic-resistant colitis, or steroid-insensitive GVHD. Our pilot data suggest safety and certain clinical effi ciency of this approach, however, requiring further observations in larger groups.
Conflicts of interest
None of the authors declare any confl icts of interest.
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Introduction
Intensive cytostatic therapy is applied as a standard treatment in malignant disorders of hematopoiesis. E.g., antitumor chemotherapy of leukemias is performed in several steps: remission induction, consolidating and supportive therapy. In cases of high-risk relapse, the patient is subject to allogeneic hematopoietic stem cell transplantation (HSCT), in order to inactivate residual cancer cells. During last 30 years, allogeneic HSCT was used in more than a million of cancer patients. As fi rst step of treatment, they receive high-dose cytostatic therapy (conditioning treatment) which is usually combined with anti-infectious therapy. The conditioning therapy causes both acute cellular immune defi ciency which recovers within months and, even, years [1]. Moreover, severe damage of oral and intestinal epithelium develops after intensive cytostatic treatment, and massive antibacterial therapy lead to alterations of gut microfl ora composition [2]. Pathogenic bacteria and their products migrate to blood plasma and may cause septicemia with detection of microbes and viruses in blood and on mucosal surfaces.
Allogeneic transplantation is generally performed from HLA-compatible familial or unrelated donor and is oft en accompanied by autoaggressive graft -versus-host disease (GVHD), an infl ammatory epithelium lesion which also contributes to immune alterations and intestinal dysfunction. Such triple eff ect of cytotoxic drugs, allogeneic immune interactions, and immune defi ciency should also change intestinal microbiota and its feedback eff ects upon host organism, including severe autoaggressive reactions [3].
The aim of our review is to specify biological and treatment- related factors causing changes of gut microbiota in the course of intensive cytostatic therapy and to delineate potential approaches to normalization for intestinal microbiome in such patients.
Previous experience with germ-free mice
The story began 50 years ago, when “gnotobiotic” (germfree) mice showed longer survival aft er irradiation at gut-damaging doses, compared to animals with normal gut microflora [4]. In a later study, the dogs subjected to lethal irradiation and bone marrow transplantation treated with antibacterial drugs proved to alleviate posttransplant complications aft er gut decontamination [5]. In 1980’s, total or selective gut decontamination (e.g., neomycin, polymyxin B amphotericin B) to prevent posttransplant infections (and maintain colonization resistance) was implemented into routine practice of hematopoietic stem cell transplantation [6]. Modern schedules for gut decontamination in cytopenic and immunocompromised patients include diff erent antibacterial, antifungal and antiviral drugs [7]. Prophylactic monotherapy with levofl oxacin also seems to decrease rates of infection aft er intensive chemotherapy in cancer [8]. Fluoroquinolone-containing schedules and other conventional gut decontamination protocols seem to be suboptimal under current epidemiological environment [9]. Th ese approaches should be directed for sparing necessary microbial diversity in gut microbiota and minimize risk for antibiotic-resistant infections.
“Normal” and changed human gut microbiota
Intestinal microbiota consists of myriads microorganisms, comprising a dynamic biological system functioning within a host organism. Human gut microbiota includes >1000 known microbial and fungal species [10]. Gut virome also contains hundreds viral species, both, phages and vertebrate viruses [11]. Over last years, possible role of the microbiota variety is described in a series of extensive review articles [12]. Generally, the major massive of intestinal microbiota may be classifi ed into several big classes: anaerobic Clostridia and mostly aerobic Bacteroides, Proteobacteria. Anaerobic clostridial species seem to perform a big deal of metabolic events in normal state, producing some essential metabolites for the host organism, e.g. short-chain fatty acids necessary for enterocyte survival and regulating immune eff ects in the host. Common changes in main classes of microbiota are associated with diff erent gastrointestinal disorders, e.g., infl ammatory bowel diseases [13].
Enteric permeability, microbial translocation and effector molecules
Viable intestinal microbiota produces big amounts of biologically active compounds which may under certain conditions penetrate from intestinal lumen via enteric wall to blood and lymph vessels. Live intestinal bacteria are thought to cross enteric/blood barrier in cases of intestinal damage caused, e.g., by intensive cytostatic treatment, or in severe immune defi ciency as it is seen in AIDS patients being a sign of the so-called bacterial translocation [14]. Bacterial components and metabolites in blood serum are known clinical markers of the patients with septicemia [15]. E.g., lipid A (lipopolysaccharide, LPS) is a component of endotoxin from Gram-negative bacteria, being detectable in blood plasma or urine. Th e LPS presence in serum suggests blood contamination with these bacteria or their fragments. Other plasma markers of septicemia are produced by the host cells (soluble CD14; LPS-binding protein etc.). LPS in clinical material is detected by in vitro test with Limulus lysate, whereas lipid A may be found and quantifi ed by means of ELISA or mass-spectrometry.
Th e 2,3-indoxyl sulfate (IS) is a useful marker of a gut dysbiosis, being produced by gut bacteria from tryptophan [16]. It is determined quantitively in blood plasma or urine by means of high-performance liquid chromatography/mass spectrometry. High IS amounts in blood are found in severe infections, intestinal dysbiosis, leakage of intestinal or hepatic barriers. Increase in other microbial metabolites, p-cresyl sulfate and trimethylamine-N-oxide is of similar diagnostic signifi cance. By the contrary, decreased blood citrulline may be a sign of intestinal damage, since it is synthesized by enterocytes [17].
Microbiota and immune response: APC and Th17 T cell network
Microbial and viral antigens, while penetrating mucosae, regional microvessels and lymph nodes, elicit local and regional polyclonal B- and T cell-mediated immune responses, thus being a key factor of normal maturation and functioning of immune system. Important role of intestinal microfl o ra in development and tuning of general immune response in humans, especially, in childhood, is extensively discussed in a number of review articles [18].
Th e mechanisms of immune maturation proceed via Th 17 and a chain of other signaling factors. Composition of gut microbiota and HLA antigens in host organism are also mutually dependent, both in normal and diseased persons, at least, in children, upon education of their immune system [19].
Hence, there are bidirectional relations between intestinal microbiota and the host immune system which may sufficiently modify the gut microbiome, along with immediate eff ects of cytostatic therapy, as well as long-term clinical outcomes, especially during hematopoietic stem cell transplantation (HSCT), due to minor diff erences in HLA antigens between donor and recipient.
Individual diversity of gut microbiota with age and dietary factors
During pregnancy, fetal intestine is sterile, being influenced by a number of external and internal factors [20, 21]. Th e extrinsic factors are – geographic area, maternal and surrounding environment bacteria, the way of childbirth – natural or by caesarean section, hygiene measures, feeding habits, drug therapies. As usual, colonizing bacteria derive from the mother – mainly vaginal and intestinal microbiota, breast milk and surrounding environment [22].
Th e intrinsic factors include neonatal genetics, bacterial mucosal receptors and interactions, intestinal pH and secretions, and immune response [24, 25].
One of the most important factors during the first months of life aff ecting the qualitative and quantitative composition of the microbiota is the fact of breast-feeding, which in addition to the energy function, provides immunoregulation [26], the digestive system functioning due to the presence of growth factors, cytokines, immunoglobulins and digestive enzymes in its composition [27].
During the fi rst and second year of life, diff erences between breast- and formula-fed infants are lost [28]. But short- and long-term eff ects of breast-feeding are much better in comparison to formula-fed infants reducing the incidence of allergic and autoimmune diseases [29], infl ammatory bowel diseases, cardiovascular diseases, obesity, type-2 diabetes [30, 31].
In the future, microbiota composition changes and its functional activity depend on nutrition features [32]. For example, the commitment to a Western diet, which typically consist of red meat, animal fat, high sugar and low fi ber food, leads to an increased number of Bacteroides phyla (mainly mucin-degradating bacteria) and Ruminococcus [33], reduced number of obligate bacteria, especially in the elderly [34]. While diet rich in fi ber correlate with larger bacterial diversity [35] and provide more functional microbiota activity, the degree of immunoregulation and cancer prevention [36].
One of the important questions is the impact of probiotics in the setting of availability to change microbiota characteristics and functioning is still controversial and depends on diagnosis and initial bacteria profi le. Probiotics are defined as «live microbial food supplements or components of bacteria which have been shown to have benefi cial eff ects on human health» and generally contain bacteria belonging to the genera Lactobacillus and Bifi dobacterium. It is shown that probiotics may have positive infl uence on immune functions, blood cholesterol decrease, vitamin synthesis, anti-cancerogenesis and anti-bacterial eff ect [37]. On the other hand, there is data indicating that probiotics are unable to colonize intestine for a long period of time, and have less efficacy in treatment of antibiotic associated diarrhea [38].
Some specific host-microbiota relations were found by a joint team from Netherlands and Russia who performed metagenomic sequencing in 1,514 subjects [39]. Using GWAS approach, they have found signifi cant associations of 9 human genome loci with microbial taxonomies and 33 loci with microbial pathways, including genome-wide signifi cance for the C-type lectin molecules CLEC4F-CD207 at 2p13.3 and CLEC4A-FAM90A1 at 12p13, and association of a functional LCT SNP with the Bifi dobacterium genus (P=3.45×10-8). These findings suggest an evidence of a gene-diet interaction for the regulation of gut Bifi dobacterium population.
However, an extensive genotype and microbiome study from the same workers based on the samples from 1,046 healthy individuals of diff erent ancestry who shared a relatively common environment has shown that the host genetics does not suffi ciently contribute to the microbiome composition [40]. Important similarities are found in the microbiota composition from genetically unrelated individuals who have common household. An estimated value of >20% of the inter- person microbiome variability is shown to be associated with dietary factors, drugs and individual anthropometry. Indeed, despite suffi cient eff ects of some gene variants, an impact of non-heritable factors, such as diet, seems to predominate the effects of host genetic background [41].
Figure 1. Overview of age-dependent human gut microbiota colonization (Note enrichment with anaerobic Firmicutes with high-fat and protein diet). Diversity of the gut microbiota increases with age until it becomes a stable adult microbiota. (Tanaka, Nakayama, 2017)
Figure 2. Microbial composition at the phylum level based on 16S rRNA gene sequences. BF = Before treatment; AF = After treatment; ATB = Antibiotics. For all antibiotics N= 21; for b-lactams N = 11; for fluoroquinolones N= 10 (Panda et al., 2017)
Microbiota affection by antimicrobial and anticancer therapy
Intensive cytostatic therapy is universally accompanied by leucopenia an temporary cellular immune defi ciency, thus causing activation of many opportunistic infections [42]. E.g., the Clostridium diffi cile infection is considered an important factor of intestinal disorders and general immune suppression in childhood [43]. Th e antibiotic-resistant bacterial strains occur at higher rate in gut, as seen from results of routine bacteriological studies.
Over last years, numerous studies show depletion of distinct bacterial groups as shown by next-generation sequencing. Load and composition of fecal microbiota were studied immediately aft er treatment in 21 patients, who received broad-spectrum antibiotics such as fl uoroquinolones and b-lactams [44]. Fecal samples were collected from all participants before treatment and one week aft er for microbial load and community composition analyses by quantitative PCR and pyrosequencing of the 16S rRNA gene. Th e study has shown a decrease in total bacterial load, and ratio of sufficient anaerobic bacteria. At the phylum level, the treatment with antibiotics increased the Bacteroidetes/Firmicutes ratio, as well as at the genera levels, mostly, due to Lachnospiraceae and Blautia exhaustion.
By contrary, experimental treatment of mice with cyclophosphamide is associated with depletion of Bacteroidetes in gut microbiota, along with accumulation of potentially harmful bacteria [45].
However, the question remains open, how combined antibacterial/anticancer therapy (e.g., cyclophosphamide) will aff ect intestinal microbiota in patients with malignancies and aff ect clinical outcomes. To this purpose, future clinical studies are required. Disturbed composition of gut microfl ora may be accompanied by remarkable functional changes of both anti-infectious and antitumor immunity [46].
Gut microbiota and acute GvHD
Acute GvHD is a common and oft en life-threatening HSCT complication caused by cytotoxic effects of donor T cells against skin and gut epithelium of the patients. GvHD severity may vary from grade 1 (mild reaction) to III-IV. A lot of genetic factors are shown to predispose for severe GvHD. Moreover, some infectious factors seem to cause or modify clinical course of GvHD, such as reactivation of CMV or EBV [1, 42].
Possible role of gut bacteria as a risk factor for GvHD is now questioned. E.g., antibacterial and cytostatic therapy before HSCT causes depletion of Clostridiales order, especially, Blautia genus. Reduction in these clostridiococci proved to be associated with higher GvHD mortality in these patients [47]. Diff erent changes of gut microbiota and relevant immune mechanisms promoting GvHD in allo-HSCT patients were recently summarized [48, 49].
Host pleiotropic genes: their presumable effects upon gut microbiota
Aft er initial optimism on predisposing role of functional gene variants in various disorders, some cautions appeared, when interpreting possible changes in genetic immune regulation, e.g., aft er hematopoietic stem cell transplantation. Th e problem is that, besides numerous gene polymorphisms of protein-encoding segments, one should consider effects of other single-nucleotide polymorphisms (SNPs) in regulatory elements and small molecules, like as microRNAs (miRNAs), and their interactions. Hence, phenotypic eff ects for most SNPs may be rather blurried and not reproducible when studied in diff erent populations and clinical series, as reviewed by Gam et al. [50].
About 100 genes or allelic variants, mostly those controlling immune functions of Th 1, Th 2, and Th 17 eff ector populations, were shown to be associated with susceptibility with infl ammatory bowel diseases (IBD), as reviewed by Basso et al. [51].
However, at the present time, current GWAS studies allowed to fi nd correlations between genotype and phenotype for a number of pleiotropic human genes which modify quite diff erent disorders, e.g., lipid disturbances and immune diseases [52]. A detailed genotype-phenotype analysis has revealed shared eff ects common for gut immune disorders (e.g., Crohn's disease, ulcerative colitis, celiac disease etc.), and lipid biology. Th ese genes concern several shared pathways including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1).
ATG16L1 and gut pathology
The ATG16L1 gene encodes an autophagy protein which is produced in many cell types, including antigen-presenting cells. Among diff erent polymorphisms, a single variant of ATG16L1 (rs2241880, T300A) may predispose for development of Crohn’s disease. Th e protective ATG16L1 allele encodes threonine at amino acid position 300 (ATG16L1*300T), whereas ATG16L1*300A encoding alanine confers higher risk for development of Crohn’s disease [53]. In human intestinal epithelium, the Crohn’s disease-associated ATG16L1 coding variant shows impaired capture of internalized Salmonella within autophagosomes. Th us, we propose that the association of ATG16L1*300A with increased risk of Crohn’s disease is due to impaired interactions with bacterial and decreased bacterial capture by autophagy.
ATG16L1 in the intestinal epithelium was shown to prevent loss of Paneth cells and exaggerated cell death in animal models of experimental infl ammatory bowel disease, and, interestingly, allogeneic hematopoietic stem cell transplantation. The mutant Atg16L1HM mice are more aff ected by graft -versus-host disease (GVHD) aft er allo-HSCT. Hence, ATG16L1 seems to keep the intestinal barrier by inhibiting epithelial cell death [54].
An elegant study was performed by Sadabad et al. [55]. The infl amed and non-infl amed sites of ileal mucosa from ATG16L1- typed patients with Crohn’s disease were studied, with respect to microbiota composition at these sites. Infl amed ileal tissue of patients homozygous for the ATG16L1 protective allele showed decreased numbers of Bacteroidaceae and Enterobacteriaceae and increased Lachnospiraceae. Upon in vitro assays, the monocytes homozygous for the ATG16L1 risk allele showed impaired killing of pathogenic E.coli under infl ammatory conditions. However, the ATG16L1 allele did not aff ect the bacterial composition in the non-infl amed ileal tissue. Th e authors suggest that the host cellular immunity seems to regulate the gut microbiota composition by genetic mechanisms.
Another study [56] has shown that the common GG variant of ATG16L1 interfered with the production of IL-1β, which was highly induced in PBMCs from patients with GG genotype by exposure to pathogenic E.coli. Th e authors have also observed that the T300A variant in patients with CD strongly increases the risk for complicated fi stulizing disease, and signifi cantly aff ects antibacterial responses in vitro. Meanwhile, any studies on the role of ATG16L1 in HSCT are absent in available literature
PD-1 gene
The PD-1 and its ligands (PD-1L) represent a system of costimulatory signal proteins that regulate activation and deactivation of T cells, modulates immune response to infectious pathogens and tissue antigens, thus mediating some autoimmune conditions [57]. PD-1 is encoded by the PDCD1 gene, being expressed on many cell types in humans. Hence, its expression may sufficiently influence both antiinfectious and antitumor response in HSCT patients.
PD-1 is a coinhibitory receptor that is inducibly expressed on T cells and B cells, natural killer T cells, and monocytes. Carriers of the A allele express lower levels of PD-1 receptor on the Treg cells (CD4+CD25+ cells) [58]. Th e variable G/A site is located in an intronic enhancer (intron 4, position 7,146) within a DNA-binding site for the RUNX1 transcription factor. Appropriate gene variant was called PD-1.3 (rs11568821). Th e common variant allele A is suggested to contribute to an aberrant transcriptional regulation of PD-1 in SLE and other autoimmune diseases.
However, typing of the PDCD1 gene may be also informative in transplantation settings. I.e., Hoff mann et al. [59] have genotyped the PD-1 variants in 469 seropositive kidney graft recipients and showed a signifi cant correlation between CMV reactivation and PD-1.3 allele A which proved to be associated with CMV infection posttransplant. Interestingly, inclusion of functional IL12B 3’UTR variants increased this association. In other study, the PD-1.3 variant was typed in 1119 kidney recipients and 181 lung recipients [60]. In 481 kidney transplants, the A allele carriers showed less common kidney graft failure than the G homozygotes. Moreover, evaluation of 85 lung recipients has shown similar results, i.e., the A-carriers had longer survival, and better function of transplanted organ. In addition, the, AA recipients had a stronger anti-CMVpp65 T-cell response than the GG-typed patients.
Effects of donor PD-1 variants upon clinical course of post-HSVCT period were presented by Santos et al. [61]. The workers have found an increased risk of grades II to IV graft -versus-host disease (GvHD) when the grafts were used from the donors homozygous for the A allele of the rs11568821 SNP. Th ose subjects comprised only 30 cases out of 1500 (ca.1.5%). Meanwhile, the PD-1.3 G>A genotype of the donor was not associated with overall survival or relapse incidence. Hence, the PD-1 gene polymorphism eff ects seemed to aff ect, mainly the GVHD immune aspect in this extensive study.
Association between PD-1 variants and sepsis outcomes was also found by Mansur et al. [62] who studied the rs11568821 SNP in 219 patients with severe sepsis. Th e 3-month mortality proved to be much higher for the GG group than for A allele carriers, with increased scores of multiple organ failure.
A number of novel inhibitors of PD-1 or PD-1 ligand are now introduced into clinical practice. In this respect, certain probiotic gut bacteria are considered a suffi cient modifying factor when treating malignancies with these immune
checkpoint inhibitory drugs [63].
FUT2 gene
Th is gene encodes fucosyl transferase, an enzyme adding a fucose residue, thus producing secretor state of H blood group antigen. Th is surface molecule also serves as a receptor for some intestinal viruses, thus the secretor state of FUT2 largely determines susceptibility to rotavirus and some other gut viral infections [64].
Additional evidence for the FUT2 gene polymorphism as a factor of rotavirus infection was found in the study by Günaydın et al. [65]. Rotavirus-specifi c antibody titers proved to be signifi cantly higher in persons with secretor FUT2 variants than in non-secretors.
A special meta-analysis (about 10,000 cases) as revealed a strong association between the rs601338 (W154X) in the FUT2 gene [66]. Th e children with the A allele, which results in a truncated FUT2 protein, had lower risk of diarrhea, presumably, due to decreased numbers of cell receptors for pathogenic viruses (e.g., rotavirus).
To characterize metabolic eff ects of FUT2 gene polymorphism upon the mucosal ecosystem, a simultaneous assessment of microbiome, meta-proteome and meta-metabolome was performed in 75 endoscopic lavage samples from the cecum and sigmoid from 39 healthy subjects with diff erent FUT2 gene status (rs601338 G>A). Th e general metagenomic analysis revealed perturbations of energy metabolism in the microbiome from the non-secretor persons, i.e., enhanced carbohydrate and lipid metabolism, altered glycan biosynthesis and depleted amino-acid metabolism. Similar changes were reproduced in mice carrying the FUT2(-) genotype [67].
However, the associations between FUT2 secretor genotype and gut microbiota diversity were not confi rmed by a recent study performed in 1190 healthy persons since no correlations were revealed for alpha-diversity, or microbial composition assessed by NGS approach [68].
Other human genes potentially changing gut microbiota
Several years ago, the group by Holler et al. [69] has discovered a distinct correlation between certain polymorphisms of TLR and NOD2/CARD gene and high incidence of acute intestinal GVHD aft er HSCT. Th ese genes encode specifi c pattern-recognition receptors for bacterial antigens and mediate acute infl ammation switched by innate mechanisms. Special studies of intestinal biopsies from the GVHD patients
have shown loss of protective CD4 T cells which was more pronounced in carriers of NOD2/CARD15 gene variants [70].
Relations of NOD/CARD system and other gut disorders is also confi rmed by the results of Hrnčířová et al. [71] concerning distinct associations between Crohn's disease and some gene variants of CARD15/NOD2 gene.
Associations between NOD/CARD polymorphisms and posttransplant infections were studied by Grube et al. [72]. Th e authors found a signifi cant association between the presence of donor NOD2 SNP13 (3016_3017insC) and the incidence of septic shock (P <002). In multivariate analysis, donor NOD2 SNP13 appeared as an independent risk factor for the incidence of septic shock aft er allo-SCT.
In a Chinese study of sepsis cohort, the authors did not found any signifi cant associations for either TLR gene polymorphisms (rs4986790 or rs4986791) with sepsis susceptibility in total analysis in any genetic models [73].
Less significant (minor) diff erences for other gene variants may be obtained in large study groups, found due to big statistics.E.g., an international group has tested 10,523 IBD cases and 5,726 non-IBD controls by means of GWAS approach using the Illumina technique [74]. Th e workers have revealed a highly signifi cant association between between Crohn’s disease and a missense variant in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 Ala391Th r, rs13107325). Th e association of this SNP with microbiota was assessed in 338 colonic mucosal lavage samples using 16S rRNA sequencing. Th e Crohn’s disease risk allele proved to be associated with altered colonic mucosal microbiome in healthy controls and the patients (p=0.0009). Among major bacterial taxa of colon microbiota, the SLC39A8 Th r391 allele carriers exhibited signifi cant depletion of, e.g., Coprococcus, Roseburia, Lachnobacteria, Faecalibacterium prausnitzii and Ruminococcus gnavus in Crohn’s disease patients.
Pro- and anti-cancer effects associated with altered composition of intestinal microbiota
Over last years, abnormal intestinal microbiota is recognized as a factor of cancer treatment effi ciency and, especially, in cancer immunotherapy [75]. Potential associations between altered gut microbiota and clinical outcomes of malignancies are studied
E.g., colonic presence of Fusobacterium nucleatum correlates with increased risk for colorectal cancer, and its overpresentation in stool is shown to be associated with higher resistance of this tumor to chemotherapy [76].
In murine experiments, it was shown that prevalence of some intestinal Gram-positive bacteria may increase effi ciency of cytostatic tumor treatment, and, vice versa, antibacterial therapy eliminating Gram(+) microbes caused a decreased response of the tumors to cyclophosphamide treatment [77]. Th e authors suggest this biological eff ect to be mediated by the Th 17 T cell network which is switched by gut microfl ora-derived antigens. Appropriate clinical study was performed in patients with chronic lymphocytic leukemia (CLL) receiving cytostatic therapy [78]. A subgroup of patients treated with antibiotics against Gram-positive bacteria showed earlier progression of malignancy and decreased long-term survival.
Vice versa, predomination of a bacterial population represented mostly of Eubacterium limosum correlated with decreased risk of relapse/progression posttransplant [79]. Eubacterium limosum belongs to anaerobic bacteria producing butyric and other short-chain fatty acids which are considered to support viability and functioning of gut epithelium and local immune response [80].
Moreover, many attempts were made to correct or replace the damaged gut microbiota with specifi c strains of Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, or other probiotics [81], causing partial clinical responses in the patients with immune disorders. Probable potentiation of immune checkpoint inhibitory (anti-PD-1) therapy will be achieved, using distinct probiotic gut bacteria [63].
Probiotics and fecal transplantation post-HSCT
Fecal transplantation as a tool for microbiota substitution was proposed centuries ago. However, clinical indications for FMT and microbial markers of FMT effi ciency were developed within last 2-5 years. Th ese indications are based on the integral assessment of gut microbial spectrum performed by diff erent NGS techniques allowing to and assess ratio between distinct bacterial classes and genera [82].
Fecal microbiota transplantation (FMT) is now proposed as a substitution correcting therapy in the disorders characterized by shift s in microbial species, or other disturbances of the gut microbiota (Crohn’s disease, nonspecifi c ulcerous colitis, persistent C.diffi cile infections). Over recent years, sporadic small studies of FMT aft er hematopoietic SCT were performed in several patients with steroid-resistant intestinal GVHD by the groups from Japan and Netherlands, showing safety and satisfactory clinical effi ciency of the treatment method [83, 84]. At our BMT clinics, we have performed small studies with 11 patients who underwent allogeneic HSCT and suff ered with multiresistant microbial infections [85]. In most of the patients treated by FMT, fast clinical response was observed, along with positive dynamics of microbial fl ora in their stool samples. Our further studies are aiming to extend indications for FMT usage aft er allo-HSCT, in order to treat bacterial complications and immune disturbances (i.e., graft -versus-host disease) which suffi ciently depends on gut microbiota changes [86].
Appropriate clinical trials on the fecal microbiota transplants (FMT) have been carried out since 2014, according to the Clinical trials.gov registry, mostly, in Crohn’s disease, non-specifi c ulcerous colitis, resistant C.diffi cile infection. A total of 46 FMT trials for various clinical indications are registered in this fi eld, mostly for the phase I (safety and tolerance).
Gut virome in normal state and after HSCT
Bacteriophages
Only limited number of works concerns gut virome as a big variety of bacteriophages and eukaryotic viruses living in human cells. A competent review by Columpsi et al. [87] highlighted the issue of the intestinal bacteria and phage equilibrium, probability of eubiosis shift s, due to the phage lytic eff ects, thus causing health disorders. Moreover, the products of bacterial lysis and viral antigens could potentially trigger some adverse infl ammatory modulations. Th ere is a large heterogeneity of phages, which are infecting, mostly, specifi c bacterial classes and are difficult for appropriate taxonomic classifi cation. Ongoing epidemiological studies of intestinal phages are mostly performed by the NGS method, i.e., parallel sequencing of multiple small fragments of DNA followed by in silico alignment and reconstruction of multiple genomes, in order to identify known and novel phage
sequences.
A recently described intestinal crassPhage with in silico estimated properties, however, with unknown incidence and epidemiological features was described several years by means of modern NGS technique and in silico digital characterization of this, previously unknown phage which is probably living in Bacteroides and is detectable in ca. 73-77% of humans , is able to vertical transmission [88]. Moreover, the authors have shown its transmission to the recipient during fecal microbiota transplantation in C.difficile infection, thus showing an opportunity of tracing its migration pathways.
Eukaryotic cell viruses
Generally, a number of RNA and DNA viruses living in eukaryotic intestinal cells are detected in normal human gut, including rotavirus, astrovirus, calicivirus, norovirus, hepatitis E, adenoviruses etc. [87]. Moreover, quite recently, multiple “novel” RNA and DNA viruses were identifi ed in gut microbiota by their specifi c gene sequences, e.g., Picornaviridae, Coronaviridae, Astroviridae, Parvoviridae members, using high-coverage NGS approach [89].
Clinical viral infections and reactivation of diff erent intestinal viruses were extensively studied in hematopoietic stem cell and organ transplantation, including adenovirus, bocavirus, coronavirus, human herpesvirus-6, lymphocytic choriomeningitis virus, measles, mumps, metapneumovirus, parainfl uenza, rotavirus, etc. [90].
Routine clinical protocols for hematopoietic stem cell transplantation include weekly or bi-weekly multiple PCR screening for herpesviruses (cytomegalovirus, Herpes simplex, Epstein-Barr virus) and, especially, adenovirus for the
fi rst 1-2 months posttransplant which correlate with diff erent life-threatening complications [91]. Virus persistence in blood or stool may require further monitoring of viral load and consider the role of pathogen in intestinal disorders (i.e., prolonged diarrhea, intestinal GVHD). A suffi cient role of altered gut virome in HSCT was shown by Legoff et al. [48]. Th e authors have undertaken a global NGS study of gut microbiota in HSCT patients over diff erent time points and have found increased proportion of picobirnavirus (PBV) sequences in stool of the patients who later developed acute enteric GVHD. Th e increased PBV levels were revealed both before and up to 1 month posttransplant.
Interestingly, filterable (potentially, viral) substances of gut microbiota may be also eff ective in fecal transplantation. A German group [92] has used stool samples passed through Seitz fi lters, thus removing all native microbes, leaving presumably viral particles and some bacterial components. Th ese fl uid preparations were delivered to intestines of the patients with C.diffi cile infection and have produced good clinical eff ect, despite absence of intact bacteria in the fecal transplant. Eff ect of such treatment, if it will be reproduced, may be dependent on bacteriophages and human viruses present in the cell-free fl uid used by the workers. Potential role of bacteriophages in posttransplant conditions is suggested in the review article by Górski et al. [93]. Th is paper contains a collection of data on positive immune-mediated eff ects of intestinal bacteriophages upon intestinal epithelial cells, thus, probably, causing mitigation of graft - versus-host disease in humans. Worthy of note, a special study with FMT in C.diffi cile infection has shown that the donor-derived bacteriophages (specifi cally, Caudovirales) were expanded to larger degree in the patients responding to FMT than in those who did not [94]. Vice versa, the FMT recipients who received donor faeces with higher Caudovirales abundance were successfully treated with FMT. Appropriate studies in HSCT setting would be of suffi cient value in future, thus evaluating role of the phage component on FMT effects.
Future prospects
Despite good current knowledge on sufficient role of intestinal microbiota in HSCT setting, some issues remain unresolved.
First of all, most studies on positive effects of microbiota were performed in experimental models, thus requiring specifi c evaluation of these facts in human patients. Secondly, when dealing with complex bacterial network of microbiota in clinical settings, we still do not know what exact microbial species (or classes) are producing eff ector molecules modifying human immune response leading to severe GvHD or associated antitumor eff ects of immune therapy. To compare them with healthy subjects, the normal ranges should be established for distinct classes of intestinal microbiota within diff erent age groups. Th irdly, the qualitative and quantitative ranges of normal intestinal microbiota should be specified by classical bacteriological and immunological diagnostics accomplished with multiplex DNA diagnostics (multiplex PCR and next-generation sequencing) of stool samples from healthy persons. As a result, the new molecular targets could be suggested for improved immune therapy of oncological diseases, especially, in childhood. A special issue bears on proven combined eff ects of the antibacterial/anticancer therapy (e.g., cyclophosphamide) upon intestinal microbiota, with appropriate consequences for early HSCT complications and risk of relapses in human leukemias, lymphomas and some pediatric malignancies.
Due to absence of notable clinical recovery in HSCT from the probiotics treatment, one may, at this step of clinical research, propose a full-microbiota replacement for treatment of severe intestinal dysbioses, i.e., introduction of normal mixed donor microbiota to the gastrointestinal tract, aiming for rapid recovery of normal microbial composition. Such experimental treatment option is a kind of biotherapy which is now eff ectively used in the patients with persistent C.diffi cile infection, intestinal bowel diseases etc. Hence, fecal microbiota transplantation is feasible in HSCT patients, fi rst of all in antibiotic-resistant colitis, or steroid-insensitive GVHD. Our pilot data suggest safety and certain clinical effi ciency of this approach, however, requiring further observations in larger groups.
Conflicts of interest
None of the authors declare any confl icts of interest.
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Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20858" ["VALUE"]=> array(2) { ["TEXT"]=> string(5856) "<p style="text-align: justify;"> Интенсивная цитостатическая терапия применяется в качестве стандартной терапии злокачественных новообразований гемопоэтической системы. Кондиционирующая терапия перед трансплантацией гемопоэтических стволовых клеток (ТГСК) приводит как к острому клеточному иммунодефициту, так и к тяжелым нарушениям кишечного эпителия, а массивная антибактериальная терапия ведет к глубоким нарушениям состава кишечной микрофлоры. Целью настоящего обзора было уточнение генетических факторов, внешних воздействий и терапевтических факторов, вызывающих изменения кишечной микробиоты в процессе интенсивной цитостатической терапии, обозначение возможных подходов к нормализации кишечного микробиома при ТГСК. Обсуждаются ранние эксперименты с безмикробными животными, описываются общепринятые взгляды на «нормальную» микробиоту кишечника человека, ее вариабельность и изменения, зависящие от возраста, диеты и генетической предрасположенности по основным классам кишечной микробиоты, т. е., анаэробных Clostridia, и более аэробных Bacteroides, Proteobacteria. Измененный состав и снижение биоразнообразия кишечной микробиоты рассматривается в качестве регулярного следствия цитостатической и антибактериальной терапии в период ТГСК. Роль порозности кишечной стенки и соответствующие эффекты на иммунную систему организма-хозяина рассматриваются в аспекте риска реакции «трансплантат против хозяина», а также возможных антирецидивных эффектов при лейкозах, связанных с изменениями состава кишечной микробиоты. Обсуждаются некоторые гены, влияющие на кишечную микробиоту, например – влияние ATG16L1, PD-1, FUT2 и других генных вариантов, которые могут влиять на эффективность ТГСК.<br> Потенциальная роль многочисленных кишечных вирусов («вирома») известна в значительно меньшей степени, в связи с относительной нехваткой данных, полученных путем секвенирования следующего поколения (NGS) бактериофагов и вирусов эукариотических клеток.<br> В заключение отмечено, что многие факты о кишечной микробиоте требуют особой оценки у человека при его лечении. Проведен ряд работ, направленных на коррекцию измененной кишечной микробиоты при различных кишечных синдромах, в том числе – с использованием отдельных пробиотических штаммов Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, и в последнее время – трансплантации фекальной микробиоты, в том числе и при дисбиозе после ТГСК. Основная проблема состоит в том, что при анализе сложных взаимодействий бактериальной микробиоты в клинических условиях мы еще не знаем, какие именно микробные виды (или классы) продуцируют эффекторные молекулы, которые модифицируют иммунный ответ, ведущий к тяжелой РТПХ или изменяющий противоопухолевый ответ иммунотерапии. Для соответствующих сравнений со здоровыми людьми следует устанавливать нормальные области значений для конкретных классов кишечной микробиоты в различных возрастных группах. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Микробиом, кишечный, кишечные бактерии, виром, трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, антибактериальное лечение, подавление микрофлоры, трансплантация кишечной микробиоты. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5778) "
Интенсивная цитостатическая терапия применяется в качестве стандартной терапии злокачественных новообразований гемопоэтической системы. Кондиционирующая терапия перед трансплантацией гемопоэтических стволовых клеток (ТГСК) приводит как к острому клеточному иммунодефициту, так и к тяжелым нарушениям кишечного эпителия, а массивная антибактериальная терапия ведет к глубоким нарушениям состава кишечной микрофлоры. Целью настоящего обзора было уточнение генетических факторов, внешних воздействий и терапевтических факторов, вызывающих изменения кишечной микробиоты в процессе интенсивной цитостатической терапии, обозначение возможных подходов к нормализации кишечного микробиома при ТГСК. Обсуждаются ранние эксперименты с безмикробными животными, описываются общепринятые взгляды на «нормальную» микробиоту кишечника человека, ее вариабельность и изменения, зависящие от возраста, диеты и генетической предрасположенности по основным классам кишечной микробиоты, т. е., анаэробных Clostridia, и более аэробных Bacteroides, Proteobacteria. Измененный состав и снижение биоразнообразия кишечной микробиоты рассматривается в качестве регулярного следствия цитостатической и антибактериальной терапии в период ТГСК. Роль порозности кишечной стенки и соответствующие эффекты на иммунную систему организма-хозяина рассматриваются в аспекте риска реакции «трансплантат против хозяина», а также возможных антирецидивных эффектов при лейкозах, связанных с изменениями состава кишечной микробиоты. Обсуждаются некоторые гены, влияющие на кишечную микробиоту, например – влияние ATG16L1, PD-1, FUT2 и других генных вариантов, которые могут влиять на эффективность ТГСК.
Потенциальная роль многочисленных кишечных вирусов («вирома») известна в значительно меньшей степени, в связи с относительной нехваткой данных, полученных путем секвенирования следующего поколения (NGS) бактериофагов и вирусов эукариотических клеток.
В заключение отмечено, что многие факты о кишечной микробиоте требуют особой оценки у человека при его лечении. Проведен ряд работ, направленных на коррекцию измененной кишечной микробиоты при различных кишечных синдромах, в том числе – с использованием отдельных пробиотических штаммов Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, и в последнее время – трансплантации фекальной микробиоты, в том числе и при дисбиозе после ТГСК. Основная проблема состоит в том, что при анализе сложных взаимодействий бактериальной микробиоты в клинических условиях мы еще не знаем, какие именно микробные виды (или классы) продуцируют эффекторные молекулы, которые модифицируют иммунный ответ, ведущий к тяжелой РТПХ или изменяющий противоопухолевый ответ иммунотерапии. Для соответствующих сравнений со здоровыми людьми следует устанавливать нормальные области значений для конкретных классов кишечной микробиоты в различных возрастных группах.
Ключевые слова
Микробиом, кишечный, кишечные бактерии, виром, трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, антибактериальное лечение, подавление микрофлоры, трансплантация кишечной микробиоты.
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Goloshchapov, Maxim A. Kucher, Alexey B. Chukhlovin<br> `" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(66) "Oleg V. Goloshchapov, Maxim A. Kucher, Alexey B. 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Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(118) "R. 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Conditioning treatment before allogeneic hematopoietic stem cell transplantation (HSCT) causes both acute cellular immune defi ciency and severe damage of gut epithelium, and massive antibacterial therapy lead to profound alterations of gut microfl ora composition. The aim of this review article was to specify environmental, genetic and treatment-related factors causing changes of gut microbiota in the course of intensive cytostatic therapy, delineating possible approaches to normalization of gut microbiome in HSCT. We discuss early experiments with germ-free organisms, describe common views on the “normal” human gut microbiota, its variability, and changes depending on age, dietary background and genetic predisposal between the main classes of gut microbiota, i.e., anaerobic Clostridia, and mostly aerobic Bacteroides, Proteobacteria. Changed composition and decreased biodiversity of gut microfl ora is regarded as a regular consequence of cytostatic and antibacterial therapies during the HSCT procedure. Role of enteric leakage, and eff ects upon immune system of host are considered in view of graft -versus-disease risk, as well as anti-cancer eff ects associated with altered composition of intestinal microbiota. Some genes aff ecting gut microbiota are discussed, e.g., eff ects of ATG16L1, PD-1, FUT2 and some other gene variants which may alter efficiency of HSCT.<br> Potential role of multiple gut viruses (virome) is known to much lesser degree, due to relative lack of data derived from next-generation sequencing (NGS) of bacteriophages and eukaryotic cell viruses.<br> In conclusion, many facts concerning gut microbiota require specifi c evaluation in human patients. E.g., a number of works was performed in order to correct altered gut microbiota in various intestinal syndromes, including specifi c probiotic strains of Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, and more recently, fecal microbiota transplantation, also in the post-HSCT dysbiosis. Th e main issue is that, when dealing with complex bacterial network of microbiota in clinical settings, we still do not know what exact microbial species (or classes) are producing eff ector molecules which modify immune response causing severe GvHD or changing the antitumor eff ects of immune therapy. To compare them with healthy subjects, the normal ranges should be established for distinct classes of intestinal microbiota within diff erent age groups. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Microbiome, intestinal, gut bacteria, virome, hematopoietic stem cell transplantation, cytostatic therapy, antibacterial treatment, microfl ora suppression, gut microbiota transplantation. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2896) "
Intensive cytostatic therapy is applied as a standard treatment in malignant disorders of hematopoiesis. Conditioning treatment before allogeneic hematopoietic stem cell transplantation (HSCT) causes both acute cellular immune defi ciency and severe damage of gut epithelium, and massive antibacterial therapy lead to profound alterations of gut microfl ora composition. The aim of this review article was to specify environmental, genetic and treatment-related factors causing changes of gut microbiota in the course of intensive cytostatic therapy, delineating possible approaches to normalization of gut microbiome in HSCT. We discuss early experiments with germ-free organisms, describe common views on the “normal” human gut microbiota, its variability, and changes depending on age, dietary background and genetic predisposal between the main classes of gut microbiota, i.e., anaerobic Clostridia, and mostly aerobic Bacteroides, Proteobacteria. Changed composition and decreased biodiversity of gut microfl ora is regarded as a regular consequence of cytostatic and antibacterial therapies during the HSCT procedure. Role of enteric leakage, and eff ects upon immune system of host are considered in view of graft -versus-disease risk, as well as anti-cancer eff ects associated with altered composition of intestinal microbiota. Some genes aff ecting gut microbiota are discussed, e.g., eff ects of ATG16L1, PD-1, FUT2 and some other gene variants which may alter efficiency of HSCT.
Potential role of multiple gut viruses (virome) is known to much lesser degree, due to relative lack of data derived from next-generation sequencing (NGS) of bacteriophages and eukaryotic cell viruses.
In conclusion, many facts concerning gut microbiota require specifi c evaluation in human patients. E.g., a number of works was performed in order to correct altered gut microbiota in various intestinal syndromes, including specifi c probiotic strains of Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, and more recently, fecal microbiota transplantation, also in the post-HSCT dysbiosis. Th e main issue is that, when dealing with complex bacterial network of microbiota in clinical settings, we still do not know what exact microbial species (or classes) are producing eff ector molecules which modify immune response causing severe GvHD or changing the antitumor eff ects of immune therapy. To compare them with healthy subjects, the normal ranges should be established for distinct classes of intestinal microbiota within diff erent age groups.
Keywords
Microbiome, intestinal, gut bacteria, virome, hematopoietic stem cell transplantation, cytostatic therapy, antibacterial treatment, microfl ora suppression, gut microbiota transplantation.
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Goloshchapov, Maxim A. Kucher, Alexey B. Chukhlovin<br> `" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(66) "Oleg V. Goloshchapov, Maxim A. Kucher, Alexey B. Chukhlovin`" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(66) "Oleg V. Goloshchapov, Maxim A. Kucher, Alexey B. Chukhlovin
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Intensive cytostatic therapy is applied as a standard treatment in malignant disorders of hematopoiesis. Conditioning treatment before allogeneic hematopoietic stem cell transplantation (HSCT) causes both acute cellular immune defi ciency and severe damage of gut epithelium, and massive antibacterial therapy lead to profound alterations of gut microfl ora composition. The aim of this review article was to specify environmental, genetic and treatment-related factors causing changes of gut microbiota in the course of intensive cytostatic therapy, delineating possible approaches to normalization of gut microbiome in HSCT. We discuss early experiments with germ-free organisms, describe common views on the “normal” human gut microbiota, its variability, and changes depending on age, dietary background and genetic predisposal between the main classes of gut microbiota, i.e., anaerobic Clostridia, and mostly aerobic Bacteroides, Proteobacteria. Changed composition and decreased biodiversity of gut microfl ora is regarded as a regular consequence of cytostatic and antibacterial therapies during the HSCT procedure. Role of enteric leakage, and eff ects upon immune system of host are considered in view of graft -versus-disease risk, as well as anti-cancer eff ects associated with altered composition of intestinal microbiota. Some genes aff ecting gut microbiota are discussed, e.g., eff ects of ATG16L1, PD-1, FUT2 and some other gene variants which may alter efficiency of HSCT.
Potential role of multiple gut viruses (virome) is known to much lesser degree, due to relative lack of data derived from next-generation sequencing (NGS) of bacteriophages and eukaryotic cell viruses.
In conclusion, many facts concerning gut microbiota require specifi c evaluation in human patients. E.g., a number of works was performed in order to correct altered gut microbiota in various intestinal syndromes, including specifi c probiotic strains of Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, and more recently, fecal microbiota transplantation, also in the post-HSCT dysbiosis. Th e main issue is that, when dealing with complex bacterial network of microbiota in clinical settings, we still do not know what exact microbial species (or classes) are producing eff ector molecules which modify immune response causing severe GvHD or changing the antitumor eff ects of immune therapy. To compare them with healthy subjects, the normal ranges should be established for distinct classes of intestinal microbiota within diff erent age groups.
Keywords
Microbiome, intestinal, gut bacteria, virome, hematopoietic stem cell transplantation, cytostatic therapy, antibacterial treatment, microfl ora suppression, gut microbiota transplantation.
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Intensive cytostatic therapy is applied as a standard treatment in malignant disorders of hematopoiesis. Conditioning treatment before allogeneic hematopoietic stem cell transplantation (HSCT) causes both acute cellular immune defi ciency and severe damage of gut epithelium, and massive antibacterial therapy lead to profound alterations of gut microfl ora composition. The aim of this review article was to specify environmental, genetic and treatment-related factors causing changes of gut microbiota in the course of intensive cytostatic therapy, delineating possible approaches to normalization of gut microbiome in HSCT. We discuss early experiments with germ-free organisms, describe common views on the “normal” human gut microbiota, its variability, and changes depending on age, dietary background and genetic predisposal between the main classes of gut microbiota, i.e., anaerobic Clostridia, and mostly aerobic Bacteroides, Proteobacteria. Changed composition and decreased biodiversity of gut microfl ora is regarded as a regular consequence of cytostatic and antibacterial therapies during the HSCT procedure. Role of enteric leakage, and eff ects upon immune system of host are considered in view of graft -versus-disease risk, as well as anti-cancer eff ects associated with altered composition of intestinal microbiota. Some genes aff ecting gut microbiota are discussed, e.g., eff ects of ATG16L1, PD-1, FUT2 and some other gene variants which may alter efficiency of HSCT.
Potential role of multiple gut viruses (virome) is known to much lesser degree, due to relative lack of data derived from next-generation sequencing (NGS) of bacteriophages and eukaryotic cell viruses.
In conclusion, many facts concerning gut microbiota require specifi c evaluation in human patients. E.g., a number of works was performed in order to correct altered gut microbiota in various intestinal syndromes, including specifi c probiotic strains of Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, and more recently, fecal microbiota transplantation, also in the post-HSCT dysbiosis. Th e main issue is that, when dealing with complex bacterial network of microbiota in clinical settings, we still do not know what exact microbial species (or classes) are producing eff ector molecules which modify immune response causing severe GvHD or changing the antitumor eff ects of immune therapy. To compare them with healthy subjects, the normal ranges should be established for distinct classes of intestinal microbiota within diff erent age groups.
Keywords
Microbiome, intestinal, gut bacteria, virome, hematopoietic stem cell transplantation, cytostatic therapy, antibacterial treatment, microfl ora suppression, gut microbiota transplantation.
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" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20858" ["VALUE"]=> array(2) { ["TEXT"]=> string(5856) "<p style="text-align: justify;"> Интенсивная цитостатическая терапия применяется в качестве стандартной терапии злокачественных новообразований гемопоэтической системы. Кондиционирующая терапия перед трансплантацией гемопоэтических стволовых клеток (ТГСК) приводит как к острому клеточному иммунодефициту, так и к тяжелым нарушениям кишечного эпителия, а массивная антибактериальная терапия ведет к глубоким нарушениям состава кишечной микрофлоры. Целью настоящего обзора было уточнение генетических факторов, внешних воздействий и терапевтических факторов, вызывающих изменения кишечной микробиоты в процессе интенсивной цитостатической терапии, обозначение возможных подходов к нормализации кишечного микробиома при ТГСК. Обсуждаются ранние эксперименты с безмикробными животными, описываются общепринятые взгляды на «нормальную» микробиоту кишечника человека, ее вариабельность и изменения, зависящие от возраста, диеты и генетической предрасположенности по основным классам кишечной микробиоты, т. е., анаэробных Clostridia, и более аэробных Bacteroides, Proteobacteria. Измененный состав и снижение биоразнообразия кишечной микробиоты рассматривается в качестве регулярного следствия цитостатической и антибактериальной терапии в период ТГСК. Роль порозности кишечной стенки и соответствующие эффекты на иммунную систему организма-хозяина рассматриваются в аспекте риска реакции «трансплантат против хозяина», а также возможных антирецидивных эффектов при лейкозах, связанных с изменениями состава кишечной микробиоты. Обсуждаются некоторые гены, влияющие на кишечную микробиоту, например – влияние ATG16L1, PD-1, FUT2 и других генных вариантов, которые могут влиять на эффективность ТГСК.<br> Потенциальная роль многочисленных кишечных вирусов («вирома») известна в значительно меньшей степени, в связи с относительной нехваткой данных, полученных путем секвенирования следующего поколения (NGS) бактериофагов и вирусов эукариотических клеток.<br> В заключение отмечено, что многие факты о кишечной микробиоте требуют особой оценки у человека при его лечении. Проведен ряд работ, направленных на коррекцию измененной кишечной микробиоты при различных кишечных синдромах, в том числе – с использованием отдельных пробиотических штаммов Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, и в последнее время – трансплантации фекальной микробиоты, в том числе и при дисбиозе после ТГСК. Основная проблема состоит в том, что при анализе сложных взаимодействий бактериальной микробиоты в клинических условиях мы еще не знаем, какие именно микробные виды (или классы) продуцируют эффекторные молекулы, которые модифицируют иммунный ответ, ведущий к тяжелой РТПХ или изменяющий противоопухолевый ответ иммунотерапии. Для соответствующих сравнений со здоровыми людьми следует устанавливать нормальные области значений для конкретных классов кишечной микробиоты в различных возрастных группах. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Микробиом, кишечный, кишечные бактерии, виром, трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, антибактериальное лечение, подавление микрофлоры, трансплантация кишечной микробиоты. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5778) "
Интенсивная цитостатическая терапия применяется в качестве стандартной терапии злокачественных новообразований гемопоэтической системы. Кондиционирующая терапия перед трансплантацией гемопоэтических стволовых клеток (ТГСК) приводит как к острому клеточному иммунодефициту, так и к тяжелым нарушениям кишечного эпителия, а массивная антибактериальная терапия ведет к глубоким нарушениям состава кишечной микрофлоры. Целью настоящего обзора было уточнение генетических факторов, внешних воздействий и терапевтических факторов, вызывающих изменения кишечной микробиоты в процессе интенсивной цитостатической терапии, обозначение возможных подходов к нормализации кишечного микробиома при ТГСК. Обсуждаются ранние эксперименты с безмикробными животными, описываются общепринятые взгляды на «нормальную» микробиоту кишечника человека, ее вариабельность и изменения, зависящие от возраста, диеты и генетической предрасположенности по основным классам кишечной микробиоты, т. е., анаэробных Clostridia, и более аэробных Bacteroides, Proteobacteria. Измененный состав и снижение биоразнообразия кишечной микробиоты рассматривается в качестве регулярного следствия цитостатической и антибактериальной терапии в период ТГСК. Роль порозности кишечной стенки и соответствующие эффекты на иммунную систему организма-хозяина рассматриваются в аспекте риска реакции «трансплантат против хозяина», а также возможных антирецидивных эффектов при лейкозах, связанных с изменениями состава кишечной микробиоты. Обсуждаются некоторые гены, влияющие на кишечную микробиоту, например – влияние ATG16L1, PD-1, FUT2 и других генных вариантов, которые могут влиять на эффективность ТГСК.
Потенциальная роль многочисленных кишечных вирусов («вирома») известна в значительно меньшей степени, в связи с относительной нехваткой данных, полученных путем секвенирования следующего поколения (NGS) бактериофагов и вирусов эукариотических клеток.
В заключение отмечено, что многие факты о кишечной микробиоте требуют особой оценки у человека при его лечении. Проведен ряд работ, направленных на коррекцию измененной кишечной микробиоты при различных кишечных синдромах, в том числе – с использованием отдельных пробиотических штаммов Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, и в последнее время – трансплантации фекальной микробиоты, в том числе и при дисбиозе после ТГСК. Основная проблема состоит в том, что при анализе сложных взаимодействий бактериальной микробиоты в клинических условиях мы еще не знаем, какие именно микробные виды (или классы) продуцируют эффекторные молекулы, которые модифицируют иммунный ответ, ведущий к тяжелой РТПХ или изменяющий противоопухолевый ответ иммунотерапии. Для соответствующих сравнений со здоровыми людьми следует устанавливать нормальные области значений для конкретных классов кишечной микробиоты в различных возрастных группах.
Ключевые слова
Микробиом, кишечный, кишечные бактерии, виром, трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, антибактериальное лечение, подавление микрофлоры, трансплантация кишечной микробиоты.
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Интенсивная цитостатическая терапия применяется в качестве стандартной терапии злокачественных новообразований гемопоэтической системы. Кондиционирующая терапия перед трансплантацией гемопоэтических стволовых клеток (ТГСК) приводит как к острому клеточному иммунодефициту, так и к тяжелым нарушениям кишечного эпителия, а массивная антибактериальная терапия ведет к глубоким нарушениям состава кишечной микрофлоры. Целью настоящего обзора было уточнение генетических факторов, внешних воздействий и терапевтических факторов, вызывающих изменения кишечной микробиоты в процессе интенсивной цитостатической терапии, обозначение возможных подходов к нормализации кишечного микробиома при ТГСК. Обсуждаются ранние эксперименты с безмикробными животными, описываются общепринятые взгляды на «нормальную» микробиоту кишечника человека, ее вариабельность и изменения, зависящие от возраста, диеты и генетической предрасположенности по основным классам кишечной микробиоты, т. е., анаэробных Clostridia, и более аэробных Bacteroides, Proteobacteria. Измененный состав и снижение биоразнообразия кишечной микробиоты рассматривается в качестве регулярного следствия цитостатической и антибактериальной терапии в период ТГСК. Роль порозности кишечной стенки и соответствующие эффекты на иммунную систему организма-хозяина рассматриваются в аспекте риска реакции «трансплантат против хозяина», а также возможных антирецидивных эффектов при лейкозах, связанных с изменениями состава кишечной микробиоты. Обсуждаются некоторые гены, влияющие на кишечную микробиоту, например – влияние ATG16L1, PD-1, FUT2 и других генных вариантов, которые могут влиять на эффективность ТГСК.
Потенциальная роль многочисленных кишечных вирусов («вирома») известна в значительно меньшей степени, в связи с относительной нехваткой данных, полученных путем секвенирования следующего поколения (NGS) бактериофагов и вирусов эукариотических клеток.
В заключение отмечено, что многие факты о кишечной микробиоте требуют особой оценки у человека при его лечении. Проведен ряд работ, направленных на коррекцию измененной кишечной микробиоты при различных кишечных синдромах, в том числе – с использованием отдельных пробиотических штаммов Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, и в последнее время – трансплантации фекальной микробиоты, в том числе и при дисбиозе после ТГСК. Основная проблема состоит в том, что при анализе сложных взаимодействий бактериальной микробиоты в клинических условиях мы еще не знаем, какие именно микробные виды (или классы) продуцируют эффекторные молекулы, которые модифицируют иммунный ответ, ведущий к тяжелой РТПХ или изменяющий противоопухолевый ответ иммунотерапии. Для соответствующих сравнений со здоровыми людьми следует устанавливать нормальные области значений для конкретных классов кишечной микробиоты в различных возрастных группах.
Ключевые слова
Микробиом, кишечный, кишечные бактерии, виром, трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, антибактериальное лечение, подавление микрофлоры, трансплантация кишечной микробиоты.
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Multiple myeloma is proliferation of malignant plasma cells, resulting in overproduction of monoclonal proteins. It is the second most common hematologic malignancy in the USA [1], and it had long been considered a cancer with poor prognosis. At the present time, long-term survival of 5 and 10 years is possible, due to improvement of chemotherapy protocols and development of ground-breaking immunotherapy. This trend allowed many hematologists to avoid allogeneic bone marrow transplant in a number of patients. Lenalidomide, bortezomib and newer drugs have proven their effi cacy in treating MM, but a subset of patients develops resistance to this treatment.
Autologous stem cell transplantation (auto-HCT) is an integrated
part of most treatment strategies. Allogeneic stem
cell transplantation (allo-HCT) is still a controversial option because of increased transplant-related mortality rates (TRM). Meanwhile, some doctors prefer allogeneic grafting rather than autologous transplantation in relapse of MM, due to long-term disease-free survival associated with allo-HCT. Some factors like chemosensitivity and karyotype influence allogeneic transplant overall survival (OS) while donor availability infl uence progression free survival (PFS) [2]. Its curative potential is linked to graft -versus-host disease (GVHD), a side eff ect of allo-HCT which may be exploited for attacking any residual tumor cells. Moreover, the T cells with chimeric antigenic receptors (CAR-T cells) are regarded as the tools for making hematologic malignancies curable within next decade. Th e question still exists, whether allogeneic transplant will be used as a treatment modality for MM when implementing relatively more safe immune therapy options, like CAR-T cells.
Autologous transplant, an old work-horse
Autologous hematopoietic stem cell transplantation (auto-HCT) was fi rst introduced in the 80s as an innovative treatment, being a preferred cellular treatment available for MM therapy. It has some advantages over allogeneic BMT and is still considered a safer option. Th e absence of immunolog-ical complications, like rejection and graft versus host disease (GVHD) is a major benefi t, but the treatment-related toxicity cannot be overlooked. Despite multiple novel agents being developed, melphalan is still the main drug used for conditioning in the absence of other less toxic alternatives. Several alternative conditioning regimens have been studied but did not show superiority [3]. One exception may be Bendamustine, but this has not been fully explored yet [4]. Several other agents like idarubicin, etoposide, busulfan, carmustine and bortezomib were also studied as a substitute for melphalan, while none of them was shown to be superior [5], some were even more toxic than melphalan alone [6, 7], and recent studies comparing melphalan and carmustine did not show any diff erence in terms of TRM [8, 9]. Furthermore, there is no universal consensus, when it comes to choice of the treatment modalities. E.g., one school recommends early double autologous transplant as based on trials that found considerable diff erence in 7-year overall survival (OS) between single vs double autologous SCT (42 vs 21% respectively) bearing in mind the low progression-free survival (PFS) in both groups (23% vs 13% respectively) [10]. Meanwhile, other workers suggest performing it as salvage treatment to allow for longer remission. Some authors claim that this strategy can lead to shorter period of disease control and carries the risk of doubling mutations over time and, consequently, increasing drug resistance of MM cells [11]. Other workers believe that salvage therapy is still acceptable, but under certain circumstances, particularly in patients with PFS>12 months, with first remission of less than 2 years duration [12].
Tandem ASCT had the rationale to avoid this possible clonal evolution. Total therapy 1 (TT1), the first tandem ASCT trial for newly diagnosed MM patients showed encouraging results. Consequently, TT II and III showed further improvement of the long-term PFS and OS survival [13].
Allogeneic Transplant
Allogeneic transplant is associated with sufficient TRM incidence. With introduction of reduced-intensity conditioning (RIC), the TRM rates could be reduced, but relapse has become a prominent problem [14]. Bensinger et al. in their retrospective review have reported a reduced TRM rate following RIC regimen, with HR of 0.22 (0.1-0.4) P<0.001, and CR 38% vs 23% when comparing to those who received myeloablative conditioning [15]. RIC regimen showed lower TRM, but similar OS rate, due to lower PFS values. A relation was found between aGVHD and non-relapse mortality (NRM) at 2 years post transplant (24% vs 37%), and both conditions were less common in patients who received RIC treatment, despite higher incidence of chronic GVHD in RIC. Further modification of the conditioning regimen by retaining its intensity and reducing the toxicity did improve the outcome significantly [16].
Th e two main indications for allogeneic transplants were considered, i.e., salvage therapy after failed autologous transplant, or its usage as a part of tandem auto-allo-HCT protocols in the newly diagnosed patients [17, 18, 20]. Th e fi rst approach was found to be associated with prolonged remission in multiple studies. In a prospective study conducted by Lavallade et al. PFS was signifi cantly higher in allogeneic HCT group as compared to the patients who received standard therapy following failed autologous transplant [19]. A similar result was also found for the high-risk patients in a retrospective study conducted by Nair, especially with lower dose of CD3+ cells infused [21]. In CIBMTR Registry, the salvage allograft patients were compared to double autotransplant cohort between 1995-2008 with inferior results, including rate of progression, observed in the salvage allograft group. In another study, when comparing 169 relapsed patients aft er autotransplant, PFS was higher in allograft group but with higher NRM and similar OS rates (54% vs 53%) [22].
Some studies, however, believe that careful donor selection may improve survival in relapsed patients [21, 23], though other options are suggested by the more recent studies [24]. Donato et al. did not fi nd statistically signifi cant diff erence in cGVHD rates between related and unrelated donor group, but higher aGVHD incidence in HCTs from unrelated donors [25, 26].
Concerning allo-SCT as a part of tandem transplant, there is still no consensus on whether it is superior to the tandem ASCT or single auto-HCT. When comparing allo-auto with tandem auto-HCT, Krishnan et al. did not fi nd better overall survival (OS) or progression-free-survival (PFS) with tandem allo-auto transplant at 3 years [27]. Among several prospective trials comparing the both treatment approaches, the three programs performed by Italian, EBMT, and DSMM working groups have revealed higher effi ciency, in terms of OS and PFS for those patients who underwent allo-SCT [26].
So far, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) has performed the largest trial which showed a weak trend for longer OS and PFS in the patients who underwent tandem ASCT, over those who had tandem auto/allo-HCT, but the results did not reach statistical signifi cance. I.e., the respective PFS rates were 46% vs 43% (P=0.67), and OS values comprised 80% vs 77%, respectively (P =0.19) [28]. Bjorkstrand et al. believe that this disparity in the results can be due to diff erences in conditioning regimen used [29]. The results of extensive available to date are summarized in Table 1.
Disappointing results of early comparative studies seem to be more encouraging with longer follow-up. Shimoni et al. claim that most studies supporting benefi ts of autologous over allogeneic transplant, do not necessarily reflect accurate results, since the follow-up period is short (an average of 3 yrs), and allogeneic transplants require longer follow-up period to show the PFS plateau [35]. In his study, the PFS plateau was seen aft er median of 6 years of follow-up with 26% PFS and 34% OS out of 50 patients. Similar results were found by El-Cheikh et al [25] at a wider age range (28-70 y.o.), with OS and PFS of 32% & 24%, respectively. Kröger et al [23] attributes this skepticism and high-failure rates of allogeneic SCT to potential inexperience and poor selection of unrelated donors for patients. In a prospective study, 95% OR and 46% CR rates are reported following allogeneic transplant with melphalan/fl udarabine-based regimen. However, PFS and OS did not diff er from those reported in patients who were treated with lenalidomide and dexamethasone, and this is likely due to high NRM revealed (25% at 1 year), despite in vivo T cell depletion with ATG. Therefore, a selection of unrelated donor is the key factor, and the importance of selecting a matched donor is unavoidable. With these factors combined together, a one-year NRM of less than 10% was achieved [16].
Table 1. Summary of results on clinical outcomes in several studies comparing auto- and allo-SCT strategies in myeloma treatment
Graft-versus-myeloma effect and donor lymphocyte infusions (DLI)
The concept behind allogeneic transplant was to employ the donor’s immune process to target MM cells in a process known as graft -versus-myeloma (GVM) eff ect but this is not inconsequential since it may be associated with GVHD. That being said, cGVHD has been considered a marker for graft -versus-myeloma eff ect, and many studies have shown this direct relationship. Th is was refl ected as better OS, and PFS when studying the patients with unrelated donors from the Italian Bone Marrow Registry. Crocchiolo et al. (2009) suggest that cGVHD, along with PBSC usage, and the number of chemotherapy rounds before allo HSCT are the factors which have infl uence upon OS [36]. Similar results were found by Donato with 36.2% survival advantage at 5 years for the patients with cGVHD [37].
Donor leukocyte infusion was developed in an eff ort to avoid second transplant in relapsed MM patients following allograft transplant. According to multiple studies, DLI is related to GVM eff ect and could safely be used to avoid a repeated transplant in relapsed patients. Multiple studies have reported improved PFS and response rate [38-40]. In a recently published study, Gröger et al. suggested using DLI as a prophylaxis to avoid relapse and improve remission. After a median follow-up of 68.7 months, they reported good 8-year PFS (43%) and OS (67%) following allogeneic transplant in 61 patients who received escalating DLI. Low GVHD incidence was also observed (33%) with no DLI related mortality [34] in the same reference. On the other hand, Edwin et al. did not observe a diff erence in the incidence of GVHD when the patients received DLI at less than one year versus > 1 year aft er BMT, as shown by Alyea et al. [40, 42]. In terms of DLI dose, some workers suggest lower cell doses for the patients with partial response, or persistent disease aft er BMT and administering higher doses to those who relapsed aft er BMT, since higher dosage meant higher GVHD rates, and, therefore, higher toxicity risks [39, 43]. Ayuk et al. suggests, by using low escalating doses as it is possible, to achieve remission in myeloma patients with relapsed, persistent or progressive disease post BMT [43]. Eeft ing et al. has found DLI eff ect to be limited to bone marrow infi ltration and not focal progression in multiple myeloma which is defi ned by new onset or increase in size of plasmacytomas and lytic bone lesions [44].
It is still controversial, whether DLI should be used with novel agents as a prophylaxis to prevent post DLI relapse or not. In fact, Van de Donk et al. proposed application of novel agents, aft er achieving clinical response in 83.3% of his patients who did not respond to DLI at the fi rst time and were treated with novel agents aft er relapse [45]. Meanwhile, Gröger et al. did not fi nd any diff erence between DLI-treated group and DLI+novel agent groups [39].
State of the art: usage of CAR-T cells, autologous and allogeneic SCT in MM
The idea of recruiting the patient’s own cells to fight tumor cells is not a new thing, but the obstacles are also numerous. One of these problems is to make the T cells capable of evading negative selection or central tolerance. This led to the development of affi nity-enhanced cells, but it was soon found that their immune escape mechanisms may cause autoimmune disorders. Accordingly, this required a design of cytotoxic cells capable of targeting specifi cally tumor cells while sparing the normal cells, being a more feasible option, thus leading to design of T cells with a chimeric antigen receptor (CAR-T cells).
The idea of CAR-T cells was based on potential usage of the patient’s own immunity to target malignant cells after genetic reprogramming the eff ector T cells, thus enabling them to detect tumor cells without aff ecting normal human antigens. They are considered a ‘living drug’, since they tend to persist for long periods of time and eventually result into signifi cant and durable destruction of malignant cells. However, this treatment is still at its early stage of development, and has long way to go, especially, in MM, as the ideal antigen that should be targeted by CAR-T cells is still to be determined.
Broad phenotypic heterogeneity of MM is an obstacle for eff ective implementation of CAR-T cells. Th is heterogeneity originates from the various MM subclones that evolve over time within the same patient’s cell population, thus making the target antigen selection even more diffi cult CD138, Igk light chain, and BCMA are considered promising target antigens that were proven to be expressed by MM cells through appropriate screening studies. CD19 can be also exploited as a potential target in leukemia and lymphoma, but not in MM, due to its negligible expression in this disorder [46]. Other antigens, like CD44v6, CD70, CD56, CD38, SLAMF7, were also present on MM cell surface, but no clinical trials were done so far. Unfortunately, most of these antigens, except of BCMA and CD138, are also expressed by other populations, like normal B lymphocytes. Hence, BCMA is the ideal target that was found to be expressed exclusively by MM cells. This was concluded aft er comparing of MM and normal cells by fl ow cytometry, IHC, and ELISA techniques, and it was recently supported by 4 clinical trials studying effects of CAR-T cells in 55 patients. Four patients developed complete remission (CR), and 30 patients showed sCR or VGPR [46]. In addition, nine trials were only published as abstracts were conducted to study the effi cacy of CAR-T cells in 156 patients. Of them, 31 patients showed complete response, 34 VGPR, and 28 achieved PR [47]. Further studies are essential to analyze T cell characteristic in MM and detect antigens that could predict response to CAR-T cells in MM patients, as it was the case in CLL. Some antigens were found predictive of good response to CAR-T cells in CLL patients, e.g., immune memory-related genes IL 6 and STAT3 signatures, whereas markers of glycolysis, and eff ector cell differentiation were found in non-responder group [48]. It is important to keep in mind the cytokine release syndrome which is a common adverse eff ect of the CAR-T cell therapy. It occurs due to massive production of cytokines like IL6, TNFa, IFNg caused by CAR-T cell activation leading to fever, hypotension, and hypoxia. Fortunately, tocilizumab (an anti IL6 antibody) may counteract the cytokine eff ect and is used as an off -label drug to control severe cases [49]. Therefore, it is reasonable to monitor the patient closely for at least 9 days, as the reaction appears within days to weeks of treatment initiation. Likewise, potential neurologic toxicity warrants monitoring patients for at least 14 days. The symptoms can range from headache and confusion to hallucinations, or dysphasia and coma [50].
Conclusion
Over several decades, diff erent treatment options were developed for MM therapy, with gradually increasing success rates. At the present time, where do we stand with cellular therapies in the treatment of Multiple Myeloma?
-
Tandem high-dose therapy with autologous stem cell rescue has been a component of several treatment schedules: it is a simple and inexpensive approach which is actively applied with suffi cient clinical effi ciency. We do not know if it is still an essential component in combination with newer drugs, but do we care? Until proven otherwise, it may stay a part of frontline of MM therapy.
-
Allogeneic SCT is a challenging and widely overlooked tool. It has shown curative potential, particularly in relapsed MM. If combined with DLI and immunomodulating agents and minimal residual disease (MRD) tracing, this approach makes immunotherapy a distinct option in MM treatment. To make allogeneic SCT wider applicable and more acceptable, a reduction in TRM is mandatory, like it has been shown feasible in pilot studies.
-
The results with CAR-T cells for MM treatment are very preliminary. We need longer observation terms, while looking whether CART cells could be comparable with results of allogeneic HCT. A forthcoming phase III study comparing best available treatment with CAR-T cell therapy in MM should bring a defi nite answer.
-
It is hard to predict the future. It is conceivable, that the plethora of new drugs might override the need for cellular therapies, like we have seen in CML, i.e. control of the disease without aiming for cure.
Conflicts of interest
None of the authors declare any confl icts of interest.
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38. Beitinjaneh AM, Saliba R, Bashir Q, Shah N, Parmar S, Hosing C, Popat U, Anderlini P, Dinh Y, Qureshi S, Rondon G, Champlin RE, Giralt SA, Qazilbash MH. Durable responses aft er donor lymphocyte infusion for patients with residual multiple myeloma following non-myeloablative allogeneic stem cell transplant. Leukemia Lymphoma. 2012; 53(8):1525-1529.
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" ["~DETAIL_TEXT"]=> string(38484) "Multiple Myeloma and the role of transplant
Multiple myeloma is proliferation of malignant plasma cells, resulting in overproduction of monoclonal proteins. It is the second most common hematologic malignancy in the USA [1], and it had long been considered a cancer with poor prognosis. At the present time, long-term survival of 5 and 10 years is possible, due to improvement of chemotherapy protocols and development of ground-breaking immunotherapy. This trend allowed many hematologists to avoid allogeneic bone marrow transplant in a number of patients. Lenalidomide, bortezomib and newer drugs have proven their effi cacy in treating MM, but a subset of patients develops resistance to this treatment.
Autologous stem cell transplantation (auto-HCT) is an integrated
part of most treatment strategies. Allogeneic stem
cell transplantation (allo-HCT) is still a controversial option because of increased transplant-related mortality rates (TRM). Meanwhile, some doctors prefer allogeneic grafting rather than autologous transplantation in relapse of MM, due to long-term disease-free survival associated with allo-HCT. Some factors like chemosensitivity and karyotype influence allogeneic transplant overall survival (OS) while donor availability infl uence progression free survival (PFS) [2]. Its curative potential is linked to graft -versus-host disease (GVHD), a side eff ect of allo-HCT which may be exploited for attacking any residual tumor cells. Moreover, the T cells with chimeric antigenic receptors (CAR-T cells) are regarded as the tools for making hematologic malignancies curable within next decade. Th e question still exists, whether allogeneic transplant will be used as a treatment modality for MM when implementing relatively more safe immune therapy options, like CAR-T cells.
Autologous transplant, an old work-horse
Autologous hematopoietic stem cell transplantation (auto-HCT) was fi rst introduced in the 80s as an innovative treatment, being a preferred cellular treatment available for MM therapy. It has some advantages over allogeneic BMT and is still considered a safer option. Th e absence of immunolog-ical complications, like rejection and graft versus host disease (GVHD) is a major benefi t, but the treatment-related toxicity cannot be overlooked. Despite multiple novel agents being developed, melphalan is still the main drug used for conditioning in the absence of other less toxic alternatives. Several alternative conditioning regimens have been studied but did not show superiority [3]. One exception may be Bendamustine, but this has not been fully explored yet [4]. Several other agents like idarubicin, etoposide, busulfan, carmustine and bortezomib were also studied as a substitute for melphalan, while none of them was shown to be superior [5], some were even more toxic than melphalan alone [6, 7], and recent studies comparing melphalan and carmustine did not show any diff erence in terms of TRM [8, 9]. Furthermore, there is no universal consensus, when it comes to choice of the treatment modalities. E.g., one school recommends early double autologous transplant as based on trials that found considerable diff erence in 7-year overall survival (OS) between single vs double autologous SCT (42 vs 21% respectively) bearing in mind the low progression-free survival (PFS) in both groups (23% vs 13% respectively) [10]. Meanwhile, other workers suggest performing it as salvage treatment to allow for longer remission. Some authors claim that this strategy can lead to shorter period of disease control and carries the risk of doubling mutations over time and, consequently, increasing drug resistance of MM cells [11]. Other workers believe that salvage therapy is still acceptable, but under certain circumstances, particularly in patients with PFS>12 months, with first remission of less than 2 years duration [12].
Tandem ASCT had the rationale to avoid this possible clonal evolution. Total therapy 1 (TT1), the first tandem ASCT trial for newly diagnosed MM patients showed encouraging results. Consequently, TT II and III showed further improvement of the long-term PFS and OS survival [13].
Allogeneic Transplant
Allogeneic transplant is associated with sufficient TRM incidence. With introduction of reduced-intensity conditioning (RIC), the TRM rates could be reduced, but relapse has become a prominent problem [14]. Bensinger et al. in their retrospective review have reported a reduced TRM rate following RIC regimen, with HR of 0.22 (0.1-0.4) P<0.001, and CR 38% vs 23% when comparing to those who received myeloablative conditioning [15]. RIC regimen showed lower TRM, but similar OS rate, due to lower PFS values. A relation was found between aGVHD and non-relapse mortality (NRM) at 2 years post transplant (24% vs 37%), and both conditions were less common in patients who received RIC treatment, despite higher incidence of chronic GVHD in RIC. Further modification of the conditioning regimen by retaining its intensity and reducing the toxicity did improve the outcome significantly [16].
Th e two main indications for allogeneic transplants were considered, i.e., salvage therapy after failed autologous transplant, or its usage as a part of tandem auto-allo-HCT protocols in the newly diagnosed patients [17, 18, 20]. Th e fi rst approach was found to be associated with prolonged remission in multiple studies. In a prospective study conducted by Lavallade et al. PFS was signifi cantly higher in allogeneic HCT group as compared to the patients who received standard therapy following failed autologous transplant [19]. A similar result was also found for the high-risk patients in a retrospective study conducted by Nair, especially with lower dose of CD3+ cells infused [21]. In CIBMTR Registry, the salvage allograft patients were compared to double autotransplant cohort between 1995-2008 with inferior results, including rate of progression, observed in the salvage allograft group. In another study, when comparing 169 relapsed patients aft er autotransplant, PFS was higher in allograft group but with higher NRM and similar OS rates (54% vs 53%) [22].
Some studies, however, believe that careful donor selection may improve survival in relapsed patients [21, 23], though other options are suggested by the more recent studies [24]. Donato et al. did not fi nd statistically signifi cant diff erence in cGVHD rates between related and unrelated donor group, but higher aGVHD incidence in HCTs from unrelated donors [25, 26].
Concerning allo-SCT as a part of tandem transplant, there is still no consensus on whether it is superior to the tandem ASCT or single auto-HCT. When comparing allo-auto with tandem auto-HCT, Krishnan et al. did not fi nd better overall survival (OS) or progression-free-survival (PFS) with tandem allo-auto transplant at 3 years [27]. Among several prospective trials comparing the both treatment approaches, the three programs performed by Italian, EBMT, and DSMM working groups have revealed higher effi ciency, in terms of OS and PFS for those patients who underwent allo-SCT [26].
So far, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) has performed the largest trial which showed a weak trend for longer OS and PFS in the patients who underwent tandem ASCT, over those who had tandem auto/allo-HCT, but the results did not reach statistical signifi cance. I.e., the respective PFS rates were 46% vs 43% (P=0.67), and OS values comprised 80% vs 77%, respectively (P =0.19) [28]. Bjorkstrand et al. believe that this disparity in the results can be due to diff erences in conditioning regimen used [29]. The results of extensive available to date are summarized in Table 1.
Disappointing results of early comparative studies seem to be more encouraging with longer follow-up. Shimoni et al. claim that most studies supporting benefi ts of autologous over allogeneic transplant, do not necessarily reflect accurate results, since the follow-up period is short (an average of 3 yrs), and allogeneic transplants require longer follow-up period to show the PFS plateau [35]. In his study, the PFS plateau was seen aft er median of 6 years of follow-up with 26% PFS and 34% OS out of 50 patients. Similar results were found by El-Cheikh et al [25] at a wider age range (28-70 y.o.), with OS and PFS of 32% & 24%, respectively. Kröger et al [23] attributes this skepticism and high-failure rates of allogeneic SCT to potential inexperience and poor selection of unrelated donors for patients. In a prospective study, 95% OR and 46% CR rates are reported following allogeneic transplant with melphalan/fl udarabine-based regimen. However, PFS and OS did not diff er from those reported in patients who were treated with lenalidomide and dexamethasone, and this is likely due to high NRM revealed (25% at 1 year), despite in vivo T cell depletion with ATG. Therefore, a selection of unrelated donor is the key factor, and the importance of selecting a matched donor is unavoidable. With these factors combined together, a one-year NRM of less than 10% was achieved [16].
Table 1. Summary of results on clinical outcomes in several studies comparing auto- and allo-SCT strategies in myeloma treatment
Graft-versus-myeloma effect and donor lymphocyte infusions (DLI)
The concept behind allogeneic transplant was to employ the donor’s immune process to target MM cells in a process known as graft -versus-myeloma (GVM) eff ect but this is not inconsequential since it may be associated with GVHD. That being said, cGVHD has been considered a marker for graft -versus-myeloma eff ect, and many studies have shown this direct relationship. Th is was refl ected as better OS, and PFS when studying the patients with unrelated donors from the Italian Bone Marrow Registry. Crocchiolo et al. (2009) suggest that cGVHD, along with PBSC usage, and the number of chemotherapy rounds before allo HSCT are the factors which have infl uence upon OS [36]. Similar results were found by Donato with 36.2% survival advantage at 5 years for the patients with cGVHD [37].
Donor leukocyte infusion was developed in an eff ort to avoid second transplant in relapsed MM patients following allograft transplant. According to multiple studies, DLI is related to GVM eff ect and could safely be used to avoid a repeated transplant in relapsed patients. Multiple studies have reported improved PFS and response rate [38-40]. In a recently published study, Gröger et al. suggested using DLI as a prophylaxis to avoid relapse and improve remission. After a median follow-up of 68.7 months, they reported good 8-year PFS (43%) and OS (67%) following allogeneic transplant in 61 patients who received escalating DLI. Low GVHD incidence was also observed (33%) with no DLI related mortality [34] in the same reference. On the other hand, Edwin et al. did not observe a diff erence in the incidence of GVHD when the patients received DLI at less than one year versus > 1 year aft er BMT, as shown by Alyea et al. [40, 42]. In terms of DLI dose, some workers suggest lower cell doses for the patients with partial response, or persistent disease aft er BMT and administering higher doses to those who relapsed aft er BMT, since higher dosage meant higher GVHD rates, and, therefore, higher toxicity risks [39, 43]. Ayuk et al. suggests, by using low escalating doses as it is possible, to achieve remission in myeloma patients with relapsed, persistent or progressive disease post BMT [43]. Eeft ing et al. has found DLI eff ect to be limited to bone marrow infi ltration and not focal progression in multiple myeloma which is defi ned by new onset or increase in size of plasmacytomas and lytic bone lesions [44].
It is still controversial, whether DLI should be used with novel agents as a prophylaxis to prevent post DLI relapse or not. In fact, Van de Donk et al. proposed application of novel agents, aft er achieving clinical response in 83.3% of his patients who did not respond to DLI at the fi rst time and were treated with novel agents aft er relapse [45]. Meanwhile, Gröger et al. did not fi nd any diff erence between DLI-treated group and DLI+novel agent groups [39].
State of the art: usage of CAR-T cells, autologous and allogeneic SCT in MM
The idea of recruiting the patient’s own cells to fight tumor cells is not a new thing, but the obstacles are also numerous. One of these problems is to make the T cells capable of evading negative selection or central tolerance. This led to the development of affi nity-enhanced cells, but it was soon found that their immune escape mechanisms may cause autoimmune disorders. Accordingly, this required a design of cytotoxic cells capable of targeting specifi cally tumor cells while sparing the normal cells, being a more feasible option, thus leading to design of T cells with a chimeric antigen receptor (CAR-T cells).
The idea of CAR-T cells was based on potential usage of the patient’s own immunity to target malignant cells after genetic reprogramming the eff ector T cells, thus enabling them to detect tumor cells without aff ecting normal human antigens. They are considered a ‘living drug’, since they tend to persist for long periods of time and eventually result into signifi cant and durable destruction of malignant cells. However, this treatment is still at its early stage of development, and has long way to go, especially, in MM, as the ideal antigen that should be targeted by CAR-T cells is still to be determined.
Broad phenotypic heterogeneity of MM is an obstacle for eff ective implementation of CAR-T cells. Th is heterogeneity originates from the various MM subclones that evolve over time within the same patient’s cell population, thus making the target antigen selection even more diffi cult CD138, Igk light chain, and BCMA are considered promising target antigens that were proven to be expressed by MM cells through appropriate screening studies. CD19 can be also exploited as a potential target in leukemia and lymphoma, but not in MM, due to its negligible expression in this disorder [46]. Other antigens, like CD44v6, CD70, CD56, CD38, SLAMF7, were also present on MM cell surface, but no clinical trials were done so far. Unfortunately, most of these antigens, except of BCMA and CD138, are also expressed by other populations, like normal B lymphocytes. Hence, BCMA is the ideal target that was found to be expressed exclusively by MM cells. This was concluded aft er comparing of MM and normal cells by fl ow cytometry, IHC, and ELISA techniques, and it was recently supported by 4 clinical trials studying effects of CAR-T cells in 55 patients. Four patients developed complete remission (CR), and 30 patients showed sCR or VGPR [46]. In addition, nine trials were only published as abstracts were conducted to study the effi cacy of CAR-T cells in 156 patients. Of them, 31 patients showed complete response, 34 VGPR, and 28 achieved PR [47]. Further studies are essential to analyze T cell characteristic in MM and detect antigens that could predict response to CAR-T cells in MM patients, as it was the case in CLL. Some antigens were found predictive of good response to CAR-T cells in CLL patients, e.g., immune memory-related genes IL 6 and STAT3 signatures, whereas markers of glycolysis, and eff ector cell differentiation were found in non-responder group [48]. It is important to keep in mind the cytokine release syndrome which is a common adverse eff ect of the CAR-T cell therapy. It occurs due to massive production of cytokines like IL6, TNFa, IFNg caused by CAR-T cell activation leading to fever, hypotension, and hypoxia. Fortunately, tocilizumab (an anti IL6 antibody) may counteract the cytokine eff ect and is used as an off -label drug to control severe cases [49]. Therefore, it is reasonable to monitor the patient closely for at least 9 days, as the reaction appears within days to weeks of treatment initiation. Likewise, potential neurologic toxicity warrants monitoring patients for at least 14 days. The symptoms can range from headache and confusion to hallucinations, or dysphasia and coma [50].
Conclusion
Over several decades, diff erent treatment options were developed for MM therapy, with gradually increasing success rates. At the present time, where do we stand with cellular therapies in the treatment of Multiple Myeloma?
-
Tandem high-dose therapy with autologous stem cell rescue has been a component of several treatment schedules: it is a simple and inexpensive approach which is actively applied with suffi cient clinical effi ciency. We do not know if it is still an essential component in combination with newer drugs, but do we care? Until proven otherwise, it may stay a part of frontline of MM therapy.
-
Allogeneic SCT is a challenging and widely overlooked tool. It has shown curative potential, particularly in relapsed MM. If combined with DLI and immunomodulating agents and minimal residual disease (MRD) tracing, this approach makes immunotherapy a distinct option in MM treatment. To make allogeneic SCT wider applicable and more acceptable, a reduction in TRM is mandatory, like it has been shown feasible in pilot studies.
-
The results with CAR-T cells for MM treatment are very preliminary. We need longer observation terms, while looking whether CART cells could be comparable with results of allogeneic HCT. A forthcoming phase III study comparing best available treatment with CAR-T cell therapy in MM should bring a defi nite answer.
-
It is hard to predict the future. It is conceivable, that the plethora of new drugs might override the need for cellular therapies, like we have seen in CML, i.e. control of the disease without aiming for cure.
Conflicts of interest
None of the authors declare any confl icts of interest.
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3 Гамбургский Университет, Гамбург, Германия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20848" ["VALUE"]=> array(2) { ["TEXT"]=> string(2125) "<p style="text-align: justify;"> Миеломная болезнь (МБ) остается пока неизлечимым злокачественным заболеванием, не отвечающим в полной мере на множество видов химио- и иммунотерапевтических методов лечения. В США ежегодно диагностируются более 20000 случаев. Трансплантация костного мозга все еще рассматривается как основной метод лечения МБ, по крайней мере в настоящее время. Очевидной необходимостью является повторное рассмотрение старых подходов к лечению с применением клеточной терапии, таких, как аутологичная или аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) и разработка новых опций, таких, как использование CAR-T-клеток.<br> Эта обзорная статья будет оценивать и обсуждать различные современные подходы к лечению МБ, путем обобщения результатов клинических исследований, рассматривать вопросы выполнимости и эффективности, и искать ответы на те из них, которые уже решены в ходе ряда клинических испытаний, проведенных с введением CAR T-клеток. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Множественная миелома, аллогенная трансплантация, аутологичная трансплантация, CAR T-клетки. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2053) "
Миеломная болезнь (МБ) остается пока неизлечимым злокачественным заболеванием, не отвечающим в полной мере на множество видов химио- и иммунотерапевтических методов лечения. В США ежегодно диагностируются более 20000 случаев. Трансплантация костного мозга все еще рассматривается как основной метод лечения МБ, по крайней мере в настоящее время. Очевидной необходимостью является повторное рассмотрение старых подходов к лечению с применением клеточной терапии, таких, как аутологичная или аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) и разработка новых опций, таких, как использование CAR-T-клеток.
Эта обзорная статья будет оценивать и обсуждать различные современные подходы к лечению МБ, путем обобщения результатов клинических исследований, рассматривать вопросы выполнимости и эффективности, и искать ответы на те из них, которые уже решены в ходе ряда клинических испытаний, проведенных с введением CAR T-клеток.
Ключевые слова
Множественная миелома, аллогенная трансплантация, аутологичная трансплантация, CAR T-клетки.
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3 University of Hamburg, Germany" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20852" ["VALUE"]=> array(2) { ["TEXT"]=> string(1053) "<p style="text-align: justify;"> Multiple myeloma is still an incurable cancer notwithstanding the myriads of chemo-and immunotherapies, There are more than 20,000 cases of MM diagnosed per year in the US. Bone marrow transplant is still considered the cornerstone for MM therapy, at least for now. The evident need is to revisit the conventional treatment approaches to cellular therapy, such as auto- and/or allogeneic hematopoietic stem cell transplantation (HCT), and develop the new options, like CAR-T cells. This review article will present and discuss diff erent approaches to modern treatment of MM, by summarizing the results of clinical studies, raising feasibility and effi ciency questions, and answering some of them which have been already resolved in numerous trials performed with CAR-T cells. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Multiple myeloma, allogeneic transplant, autologous transplant, CAR-T cells. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(987) "
Multiple myeloma is still an incurable cancer notwithstanding the myriads of chemo-and immunotherapies, There are more than 20,000 cases of MM diagnosed per year in the US. Bone marrow transplant is still considered the cornerstone for MM therapy, at least for now. The evident need is to revisit the conventional treatment approaches to cellular therapy, such as auto- and/or allogeneic hematopoietic stem cell transplantation (HCT), and develop the new options, like CAR-T cells. This review article will present and discuss diff erent approaches to modern treatment of MM, by summarizing the results of clinical studies, raising feasibility and effi ciency questions, and answering some of them which have been already resolved in numerous trials performed with CAR-T cells.
Keywords
Multiple myeloma, allogeneic transplant, autologous transplant, CAR-T cells.
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Bone marrow transplant is still considered the cornerstone for MM therapy, at least for now. The evident need is to revisit the conventional treatment approaches to cellular therapy, such as auto- and/or allogeneic hematopoietic stem cell transplantation (HCT), and develop the new options, like CAR-T cells. This review article will present and discuss diff erent approaches to modern treatment of MM, by summarizing the results of clinical studies, raising feasibility and effi ciency questions, and answering some of them which have been already resolved in numerous trials performed with CAR-T cells. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Multiple myeloma, allogeneic transplant, autologous transplant, CAR-T cells. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(987) "Multiple myeloma is still an incurable cancer notwithstanding the myriads of chemo-and immunotherapies, There are more than 20,000 cases of MM diagnosed per year in the US. Bone marrow transplant is still considered the cornerstone for MM therapy, at least for now. The evident need is to revisit the conventional treatment approaches to cellular therapy, such as auto- and/or allogeneic hematopoietic stem cell transplantation (HCT), and develop the new options, like CAR-T cells. This review article will present and discuss diff erent approaches to modern treatment of MM, by summarizing the results of clinical studies, raising feasibility and effi ciency questions, and answering some of them which have been already resolved in numerous trials performed with CAR-T cells.
Keywords
Multiple myeloma, allogeneic transplant, autologous transplant, CAR-T cells.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(987) "Multiple myeloma is still an incurable cancer notwithstanding the myriads of chemo-and immunotherapies, There are more than 20,000 cases of MM diagnosed per year in the US. Bone marrow transplant is still considered the cornerstone for MM therapy, at least for now. The evident need is to revisit the conventional treatment approaches to cellular therapy, such as auto- and/or allogeneic hematopoietic stem cell transplantation (HCT), and develop the new options, like CAR-T cells. This review article will present and discuss diff erent approaches to modern treatment of MM, by summarizing the results of clinical studies, raising feasibility and effi ciency questions, and answering some of them which have been already resolved in numerous trials performed with CAR-T cells.
Keywords
Multiple myeloma, allogeneic transplant, autologous transplant, CAR-T cells.
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Миеломная болезнь (МБ) остается пока неизлечимым злокачественным заболеванием, не отвечающим в полной мере на множество видов химио- и иммунотерапевтических методов лечения. В США ежегодно диагностируются более 20000 случаев. Трансплантация костного мозга все еще рассматривается как основной метод лечения МБ, по крайней мере в настоящее время. Очевидной необходимостью является повторное рассмотрение старых подходов к лечению с применением клеточной терапии, таких, как аутологичная или аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) и разработка новых опций, таких, как использование CAR-T-клеток.
Эта обзорная статья будет оценивать и обсуждать различные современные подходы к лечению МБ, путем обобщения результатов клинических исследований, рассматривать вопросы выполнимости и эффективности, и искать ответы на те из них, которые уже решены в ходе ряда клинических испытаний, проведенных с введением CAR T-клеток.
Ключевые слова
Множественная миелома, аллогенная трансплантация, аутологичная трансплантация, CAR T-клетки.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2053) "
Миеломная болезнь (МБ) остается пока неизлечимым злокачественным заболеванием, не отвечающим в полной мере на множество видов химио- и иммунотерапевтических методов лечения. В США ежегодно диагностируются более 20000 случаев. Трансплантация костного мозга все еще рассматривается как основной метод лечения МБ, по крайней мере в настоящее время. Очевидной необходимостью является повторное рассмотрение старых подходов к лечению с применением клеточной терапии, таких, как аутологичная или аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) и разработка новых опций, таких, как использование CAR-T-клеток.
Эта обзорная статья будет оценивать и обсуждать различные современные подходы к лечению МБ, путем обобщения результатов клинических исследований, рассматривать вопросы выполнимости и эффективности, и искать ответы на те из них, которые уже решены в ходе ряда клинических испытаний, проведенных с введением CAR T-клеток.
Ключевые слова
Множественная миелома, аллогенная трансплантация, аутологичная трансплантация, CAR T-клетки.
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Introduction
Graft -versus-host disease (GVHD) is one the most life-threatening complications in allogeneic stem cell transplantation (HSCT). With more the 40000 transplants per year, more than 10 thousand patients have this complication [1, 2]. Clinically signifi cant forms of GVHD occur in 20-50% of HSCT recipients, and it is associated with signifi cant mortality and morbidity reaching 30% in severe cases [3, 4]. Only a few large studies have been published with analysis of GVHD risk factors.
Flowers et al. in the cohort of 2941 related and unrelated graft recipients has demonstrated that unrelated donor, HLA mismatch, female donor in male recipient and donor age were the risk factors for both acute and chronic GVHD, while intensity of the conditioning was a predictor of acute GVHD, whereas patient age and peripheral blood stem cell (PBSC) graft ing were the predictors of the chronic GVHD. Also GVHD was less frequent in CML than in acute leukemia. Th e GVHD prophylaxis with antithymocyte immunoglobulin (ATG) did not reach statistical signifi cance [5]. High cellularity of the graft and high prevalence of CD3-positive cells in the graft was another predictor of acute GVHD with conventional prophylaxis, especially in PBSC recipients [6]. In another large study, the use of PBSC compared to bone marrow (BM) was the risk factor for both acute and chronic GVHD [7].
The Center for International Blood and Marrow Transplant Research (CIBMTR) study with data from 226 centers has identifi ed total body irradiation PBSC, ethnicity, poor performance study and positive cytomegalovirus status of donor and recipient as the signifi cant risk factors of acute GVHD [7]. Th e study also showed that ABO incompatibility was not a signifi cant factor, and the incidence of GVHD in CML is higher probably due to transplantation techniques.
The abovementioned studies were conducted relatively long ago, and were based on population of patients receiving predominantly cyclosporine and methotrexate (MTX) as prophylaxis, and ATG in unrelated donors. However, transplantation technologies have signifi cantly evolved over time. Novel prophylaxis regimens have been introduced, like mTOR inhibitors [8], posttransplant cyclophosphamide (PTCy) [9], TCR alpha/beta cell depletion [10]. No studies have been published on risk factors of GVHD with these novel approaches. In the present study, we searched for risk factors in two large cohorts of patients, one with conventional prophylaxis based on calcineurin inhibitors (CNIs) with MTX/mycophenolate mofetil (MMF) and other, with PTCy prophylaxis. Th e purpose of this study was to evaluate whether GVHD prophylaxis does change the pattern of risk
factors.
Patients and methods
One thousand thirteen adult patients transplanted at the First State I. Pavlov Medical University from 2006 to 2017 were included into the study. All the patients were graft ed either from matched related donor (32%) or unrelated donor (68%). In this group, 470 patients received prophylaxis with PTCy, and 543 were subjected to conventional prophylaxis (Table 1). Only patients who successfully engraft ed were included in the analysis.
GVHD prophylaxis under conventional regimen included tacrolimus with target concentration of 5 to 15 ng/ml, starting from day-1 until day+120, or cyclosporine A with target concentrations of 150 to 350 ng/ml, starting from day-1 until day+120. Th e second agent was either MMF 30 mg/kg (day -1 to day+30), or methotrexate 15 mg/m2 (day+1, 10 mg/m2; day +3, 6). Th e recipients of unrelated graft s did also receive ATG (ATGAM, Pfi zer, Inc.), at 20 mg/kg from day -3 until day -1. In the PTCy group, the prophylaxis consisted of single-agent cyclophosphamide (50 mg/kg) on days +3,+4 for matched related or unrelated bone marrow. In recipients of PBSCs, we used cyclophosphamide (50 mg/kg) on days +3,+4 followed by tacrolimus and MMF (30mg/kg) starting on day +5. In the mismatched graft s, the dose of MMF was increased to 45 mg/kg. Myeloablative conditioning (MAC) in conventional prophylaxis group was performed with oral busulfan (16 mg/kg), and cyclophosphamide (120 mg/kg). In the PTCy group, the majority of patients received MAC containing fl udarabine 180 mg/m2 and busulfan 14 mg/kg. Reduced-intensity conditioning (RIC) was performed with oral busulfan (8 mg/kg) and fl udarabine (180 mg/m2). Minority of patients received conditioning with melphalan (140 mg/m2) and fl udarabine (150 mg/m2. RIC was performed in patients, who were either older than 40 years, had HSCT-specifi c co-morbidity index (HCT-CI)≥2, or exhibited, at least, grade 3 hepatotoxicity during the induction therapy. Supportive care did not diff er for the two prophylaxis arms.
Statistical analysis
Th e Consensus Conference criteria were used for acute GVHD grading [11] and National Institutes of Health criteria were used for chronic GVHD grading [12]. Diagnosis of skin GVHD was established either clinically or histologically, the diagnosis of liver GVHD was assessed clinically, whereas gastrointestinal GVHD was specifi ed by pathological examination. Incidence of acute and chronic GVHD was evaluated with cumulative incidence estimates. Time frame for acute GVHD was 125 days, for chronic GVHD, 2 years. Evaluation of risk factors was performed by means of Gray test. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate evaluation and analysis of continuous variables were done using Fine and Grey regression. Th e variables were selected for the multivariate analysis in case of signifi cance <0.15 obtained in the univariate mode. Th e cutoff levels for continuous variables were determined in ROC analysis with maximal sum of sensitivity and specifi city as a criterion. Th e analyses were conducted in SAS 9.3 (SAS Institute, Inc.).
Results
The conventional prophylaxis group comprised 199 recipients of matched related graft s and 344 subjects were transplanted from unrelated donors. The PTCy group consisted of 104 matched related transplants, and 27 matched unrelated HSCTs, with single-agent PTCy prophylaxis. 338 patients received combined prophylaxis with PTCy, tacrolimus and MMF. Among the evaluated patients, 93.4% has engraft ed. Among the engraft ed patients, 436 received PTCy prophylaxis and 485, conventional GVHD prophylaxis, with a fi veyear survival of 47%. Incidence of acute GVHD in the whole group was 43.9%. Of them, 18.6% had grade I; 9.8%, grade II; 12.6%, grade III, and 3% had grade IV GVHD. Th e incidence of chronic GVHD was 31.6%, including 12.6% with mild; 9%, moderate degree, and 10% showed severe GVHD according to NIH criteria. Th e most common organs involved in chronic GVHD were skin, mucosa, eyes, gastrointestinal tract (GIT) and liver (Fig. 1). Incidence of acute GVHD in the PTCy group was 35%; grade II-IV acute GVHD, 15%; chronic GVHD, 29%. Moderate and severe chronic GVHD was registered in 18% of the cases. Similar incidence rates (resp., 53%, 35%, 35% and 30%) were noted for conventional prophylaxis.
Table 1. Patients’ characteristics in the study group
AML= acute myeloblastic leukemia; ALL =acute lymphoblastic leukemia; CML= chronic myeloid leukemia; HL= Hodgkin lymphoma; MDS= myelodysplastic syndrome; АА=aplastic anemia; NHL=non-Hodgkin lymphoma MF=myelofi brosis; MPN=myeloproliferative neoplasm; CLL=chronic lymphoid leukemia; MAC=myeloablative regimen; RIC =reduced-intensity conditioning.
Figure 1. The incidence and severity of acute (A) and chronic GVHD (B). The incidence of organ involvement is calculated only for the patients who developed GVHD
Figure 2. Risk factors of acute GVHD grade II-IV after conventional prophylaxis (A) and posttransplant cyclophosphamide (B). Number of CD34+ cells in the graft, age and BMI are continuous variables, all the others are logistic
For the conventional prophylaxis group, the following factors were revealed in the univariate analysis with signifi cance >0.15 for acute GVHD grade II-IV development: unrelated donor (p<0.0001), salvage group (p=0.0014), number of HSCT (p=0.1064), ABO incompatibility (p=0.0709), cytomegalovirus (CMV) serostatus (p=0.1487), graft source (p=0.0004 conditioning intensity (p=0.0003), alkylating agents in the conditioning (0.1377), age of the recipient (0.0002), CD34 cell number in the graft (p<0.0001), engraft - ment time (p<0.0001), diagnosis (p=0.0379), body mass index (BMI) (p=0.0220). Th ese parameters were included into the multivariate model where only unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96-0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and engraft ment before day +15 (HR 1.55, 95%CI 1.08-2.22) signifi cantly affected the incidence of acute GVHD grade II-IV (Figure 2A). Th e BMI cut-off value was 28 kg/m2 indicating that obese patients had less acute GVHD. Despite common risk factor of graft source, the fast engraft ment was more signifi cant than the graft source factor (p=0.48), despite the fact that fast engraft ment occurred more oft en in the PBSC recipients (32% vs 17%, p<0.0001).
In the univariate analysis of PTCy group, only unrelated donor (p=0.0170), HLA matching (p=0.0347), number of HSCT (p=0.0592), recipient gender (p=0.0592), CMV serostatus (p=0.0592), female donor for male recipient (p=0.0706), time of engraft ment (p=0.0037), and time from diagnosis to transplant were shown to be signifi cant factors (p<0.0001). Since the recipient gender was signifi cant because of female-male combination, only that factor was included in the multivariate analysis. Also in ROC analysis, the cut-off for engraft ment time was diff erent: 20 days instead of 15. Th ese parameters were added to the multivariate model where CMV serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Th e highest incidence was in the -/- pair of donor / recipient (32%), lower in the +/- pair (20%) and the lowest in the CMV-positive recipients (13% with +/+ pair vs 15% with -/+ pair). Th e univariate analysis in conventional prophylaxis group revealed unrelated donor (p=0.0002), salvage group (p=0.0635), cytomegalovirus serostatus (p=0.0248), graft source (p<0.0001), age (p=0.1360), number of CD34 cells in the graft (p=0.0047), engraft ment at <15 days (p=0.0013), time from diagnosis to transplantation (p=0.1151), diagnosis (p=0.0205) and previous acute GVHD (p<.0001) as signifi cant factors for moderate and severe chronic GVHD. In the PTCy group, the univariate analysis revealed unrelated donor (p=0.0980), donor gender (p=0.0138), graft source (p=0.0805), male recipient with female donor (p=0.1082), number of CD34+ cells in the graft (p=0.0272), time to engraft ment (p=0.0302) and previous acute GVHD (p=0.0929), as predisposing factors for chronic GVHD. In the multivariate model with conventional GVHD prophylaxis, only PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37) were signifi cant risk factors for moderate and severe chronic GVHD (Figure 3A).
Figure 3. Risk factors for moderate and severe chronic GVHD with conventional prophylaxis (A) and posttransplantation cyclophosphamide (B)
Modeling in the PTCy group demonstrated only a weak statistical signifi cance for previous acute GVHD (HR 1.59, 95%CI 0.99-2.54), while all the other factors were non-significant (Figure 3B).
Regarding mild acute GVHD (grade I-II) which is usually favorable for prognosis in the conventional prophylaxis group, only the CD34 cell dose increased the probability of this condition (HR 1.08, 95%CI 1.01-1.150, р=0.0133). The other variables were not signifi cantly different. With PTCy prophylaxis, the unrelated donorship was associated with increased probability of grade I-II acute GVHD (HR 3.26, 95%CI 1.26-8.39, p=0.0145). Also a combination of a female donor/ male recipient had week statistical signifi cance (HR 1.87, 0.94-3.72, p=0.0761). No predictors were determined for mild chronic GVHD in conventional prophylaxis patients, whereas, with PTCy, the CMV-positive recipient serostatus was protective against this condition (HR 0.675, 0.496-0.918, p=0.0123). Mild chronic GVHD was lowest in +/+ CMV positive donor/ recipient (6%), being highest in -/+ (15%) and +/- (19%) combinations. In the both CMV-negative pairs, mild chronic GVHD rate was also substantial (14%).
Discussion
In this relatively large study, we have confi rmed that the novel prophylaxis regimens may dramatically change the landscape of risk factors which was not demonstrated before. Previous registry studies mostly documented only evolutional changes in the risk factors due to other aspects of HSCT. In the era of only BM transplantation from matched siblings with cyclosporine and methotrexate as prophylaxis, the predominant risk factors were female donor for male recipient, pregnancy history and older recipient age [13]. Th e subsequent CIBMTR study identifi ed the risk factors of PBSC use, ethnicity, TBI versus busulfan-based conditioning, and positive CMV serostatus [7]. Aft er broad introduction of unrelated transplants, it became obvious that GVHD incidence is higher than aft er sibling transplants [14]. Additional risks of GVHD are associated with partial HLA mismatches [15] and non-HLA allele mismatches [16]. Furthermore, the donor age was also identifi ed as risk factor in unrelated HSCT [17]. Nonetheless the recent mathematical analysis indicates that the predictive potential of clinical parameters is relatively low [18]. Thus, the risk factors of GVHD were slowly evolving, due to implementation of novel cell sources and donor types. We, however, confi rm that the use of PTCy completely abolished the previously signifi cant risk factors. It has been previously published that HLA matching is not a signifi cant factor with PTCy prophylaxis [19], and this was confirmed in the current study. Nonetheless, the diff erence between matched sibling and unrelated donor had a tendency to signifi cance, which was also confirmed in our group of patients. What was not established earlier is the preventive
role of CMV-positive serology in recipient, despite a weak statistical trend in the EBMT study [20]. Th e probable reason for that is diff erent prevalence of CMV seropositivity in Russia, Europe and the USA. In Russia, the CMV seroprevalence is above 85% [21, 22, 23]. Th e CMV seropositivity is unlikely to represent the reason for diff erences, but, rather, it may be a consequence of changes in immune system that, probably, led to decreased GVHD incidence. It was demonstrated that CMV causes expansion of T-regulatory cells [24] and upregulation of IL-33 pathway, which protects against lethal GVHD in animal models [25, 26]. Th e signifi cance of this factor with no such evidence for conventional prophylaxis [7] indicates the presence of different immunological mechanisms behind PTCy prophylaxis that still should be elucidated.
The risk factors identifi ed for moderate and severe chronic GVHD with conventional prophylaxis were similar to the ones previously reported [27, 28]. Th e history of severe acute GVHD was the most predominant risk factor. However, no risk factors were identifi ed for PTCy, probably due to low incidence of this complication and low incidence of preceding acute GVHD in the study cohort. Contrary to this data, the European Registry Study defi ned recipient age, use of PBSC and combination prophylaxis as the risk factors [20]. Th e diff erences might be due to diff erent PTCy schedule (day +3, +5), use of cyclosporine instead of tacrolimus, duration
of immunosuppression [29]. Th e absence of diff erences between PBSC and BM is explained by single-agent PTCy prophylaxis in the matched bone marrow group and combination with tacrolimus and MMF in the PBSC group, which alleviated the diff erences.
In conclusion, this study identified the changing pattern of GVHD risk factors with introduction of novel prophylaxis regimens in related and unrelated HSCT graft s. Further studies are required to elucidate the biological mechanisms behind these changes.
Conflicts of interest
No conflicts of interest are reported by the authors.
References
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2. D'Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR summary slides, 2017. Available at: www.cibmtr.org, as of 28/07/18.
3. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, Sanders JE, Witherspoon RP, Storb R, Appelbaum FR, Martin PJ. Th erapy for chronic graft -versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood. 2002;100(1):48-51.
4. Saliba RM, Couriel DR, Giralt S, Rondon G, Okoroji GJ, Rashid A, Champlin RE, Alousi AM. Prognostic value of response aft er upfront therapy for acute GVHD. Bone Marrow Transplant. 2012;47(1):125-131.
5. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, Pereira SE, Nash RA, Mielcarek M, Fero ML, Warren EH, Sanders JE, Storb RF, Appelbaum FR, Storer BE, Martin PJ. Comparative analysis of risk factors for acute graft -versus-host disease and for chronic graft -versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117(11):3214-3219.
6. Czerw T, Labopin M, Schmid C, Cornelissen JJ, Chevallier P, Blaise D, Kuball J, Vigouroux S, Garban F, Lioure B, Fegueux N, Clement L, Sandstedt A, Maertens J, Guillerm G, Bordessoule D, Mohty M, Nagler A. High CD3+ and CD34+ peripheral blood stem cell graft s content is associated with increased risk of graft -versus-host disease without benefi cial eff ect on disease control aft er reduced-intensity conditioning allogeneic transplantation from matched unrelated donors for acute myeloid leukemia - an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Oncotarget. 2016;7(19):27255-27266.
7. Hahn T, McCarthy PL Jr, Zhang MJ, Wang D, Arora M, Frangoul H, Gale RP, Hale GA, Horan J, Isola L, Maziarz RT, van Rood JJ, Gupta V, Halter J, Reddy V, Tiberghien P, Litzow M, Anasetti C, Pavletic S, Ringden O. Risk factors for acute graft -versus-host disease aft er human leukocyte antigen- identical sibling transplants for adults with leukemia. J Clin Oncol. 2008;26(35):5728-34.
8. Cutler C, Antin JH. Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation. Bone Marrow Transplant. 2004;34(6):471-476.
9. Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R, Huff CA, Borrello I, Matsui W, Powell JD, Kasamon Y, Goodman SN, Hess A, Levitsky HI, Ambinder RF, Jones RJ, Fuchs EJ. High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft -versus-host disease. Blood. 2010;115(16):3224-3230.
10. Chaleff S, Otto M, Barfi eld RC, Leimig T, Iyengar R, Martin J, Holiday M, Houston J, Geiger T, Huppert V, Handgretinger R. A large-scale method for the selective depletion of alphabeta T lymphocytes from PBSC for allogeneic transplantation. Cytotherapy. 2007;9(8):746-754.
11. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Th omas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15:825-828.
12. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft -versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11:945-956.
13. Gale RP, Bortin MM, van Bekkum DW, Biggs JC, Dicke KA, Gluckman E, Good RA, Hoff mann RG, Kay HE, Kersey JH, et al. Risk factors for acute graft -versus-host disease. Br J Haematol. 1987;67(4):397-406.
14. Bradley BA, Hows JM, Gore SM, Bidwell JL, Clay T, Downie TR, Gluckman E, Howard MR, Laundy GJ. Current status of unrelated-donor bone marrow transplantation. Th e International Marrow Unrelated Search and Transplant (IMUST) Study. Clin Transpl. 1992:91-107.
15. Morishima Y, Sasazuki T, Inoko H, Juji T, Akaza T, Yamamoto K, Ishikawa Y, Kato S, Sao H, Sakamaki H, Kawa K, Hamajima N, Asano S, Kodera Y. Th e clinical signifi cance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002; 99(11):4200-4216.
16. Chukhlovin AB. Beyond HLA system: non-HLA gene alleles of donor origin may infl uence risk of immune allo- HSCT complications. Cell Th er Transplant. 2017; 6(2): 36-51.
17. Kollman C, Howe CW, Anasetti C, Antin JH, Davies SM, Filipovich AH, Hegland J, Kamani N, Kernan NA, King R, Ratanatharathorn V, Weisdorf D, Confer DL. Donor characteristics as risk factors in recipients aft er transplantation of bone marrow from unrelated donors: the eff ect of donor age. Blood. 2001;98(7):2043-2051.
18. Lee C, Haneuse S, Wang HL, Rose S, Spellman SR, Verneris M, Hsu KC, Fleischhauer K, Lee SJ, Abdi R. Prediction of absolute risk of acute graft -versus-host disease following hematopoietic cell transplantation. PLoS One. 2018;13(1):e0190610.
19. Kasamon YL, Luznik L, Leff ell MS, Kowalski J, Tsai HL, Bolaños-Meade J, Morris LE, Crilley PA, O'Donnell PV, Rossiter N, Huff CA, Brodsky RA, Matsui WH, Swinnen LJ, Borrello I, Powell JD, Ambinder RF, Jones RJ, Fuchs EJ. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: eff ect of HLA disparity on outcome. Biol Blood Marrow Transplant. 2010;16(4):482-489.
20. Ruggeri A, Labopin M, Bacigalupo A, Afanasyev B, Cornelissen JJ, Elmaagacli A, Itala-Remes M, Blaise D, Meijer E, Koc Y, Milpied N, Schouten HC, Kroeger N, Mohty M, Nagler A. Post-transplant cyclophosphamide for graft -versushost disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT. J Hematol Oncol. 2018;11(1):40. doi: 10.1186/s13045-018-0586-4.
21. Lantos PM, Hoff man K, Permar SR,, Jackson P, Hughes BL, Swamy GK. Geographic disparities in cytomegalovirus infection during pregnancy. J Pediatric Infect Dis Soc. 2017;6(3):e55-e61.
22. Lachmann R, Loenenbach A,, Waterboer T, Brenner N, Pawlita M, Michel A, Th amm M, Poethko-Müller C, Wichmann O, Wiese-Posselt M. Cytomegalovirus (CMV) seroprevalence in the adult population of Germany. PLoS One. 2018;13(7):e0200267.
23. Kisteneva LB. Clinical and laboratory features of cytomegalovirus and NS viral infection in pregnant women and newborns: Development of therapeutic and prophylactic measures. 2001. Th e Ph.D. Th esis, Moscow (In Russian).
24. Almanan M, Raynor J, Sholl A, Wang M, Chougnet C, Cardin RD, Hildeman DA. Tissue-specific control of latent CMV reactivation by regulatory T cells. PLoS Pathog. 2017;13(8):e1006507.
25. Popovic B, Golemac M, Podlech J, Zeleznjak J, Bilic-Zulle L, Lukic ML, Cicin-Sain L,, Reddehase MJ, Sparwasser T, Krmpotic A, Jonjic S. IL-33/ST2 pathway drives regulatory T cell-dependent suppression of liver damage upon cytomegalovirus infection. PLoS Pathog. 2017;13(4):e1006345.
26. Matta BM, Reichenbach DK, Zhang X, Mathews L, Koehn BH, Dwyer GK, Lott JM, Uhl FM, Pfeifer D, Feser CJ, Smith MJ, Liu Q, Zeiser R, Blazar BR, Turnquist HR. Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. Blood. 2016;128(3):427-439.
27. Grube M, Holler E, Weber D, Holler B, Herr W, Wolff D.Risk factors and outcome of chronic graft -versus-host disease after allogeneic stem cell transplantation: results from a single-center observational study. Biol Blood Marrow Transplant. 2016;22(10):1781-1791.
28. Remberger M, Kumlien G, Aschan J, Barkholt L, Hentschke P, Ljungman P, Mattsson J, Svennilson J, Ringden O. Risk factors for moderate-to-severe chronic graft -versushost disease aft er allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2002;8(12):674-682.
29. Chiusolo P, Bug G, Olivieri A, Brune M, Mordini N, Alessandrino PE, Dominietto A, Raiola AM, Di Grazia C, Gualandi F, Van Lint MT, Ferrara F, Finizio O, Angelucci E, Bacigalupo A. A Modifi ed post-transplant cyclophosphamide regimen, for unmanipulated haploidentical marrow transplantation, in acute myeloid leukemia: a multicenter study. Biol Blood Marrow Transplant. 2018;24(6):1243-1249.
" ["~DETAIL_TEXT"]=> string(28523) "Introduction
Graft -versus-host disease (GVHD) is one the most life-threatening complications in allogeneic stem cell transplantation (HSCT). With more the 40000 transplants per year, more than 10 thousand patients have this complication [1, 2]. Clinically signifi cant forms of GVHD occur in 20-50% of HSCT recipients, and it is associated with signifi cant mortality and morbidity reaching 30% in severe cases [3, 4]. Only a few large studies have been published with analysis of GVHD risk factors.
Flowers et al. in the cohort of 2941 related and unrelated graft recipients has demonstrated that unrelated donor, HLA mismatch, female donor in male recipient and donor age were the risk factors for both acute and chronic GVHD, while intensity of the conditioning was a predictor of acute GVHD, whereas patient age and peripheral blood stem cell (PBSC) graft ing were the predictors of the chronic GVHD. Also GVHD was less frequent in CML than in acute leukemia. Th e GVHD prophylaxis with antithymocyte immunoglobulin (ATG) did not reach statistical signifi cance [5]. High cellularity of the graft and high prevalence of CD3-positive cells in the graft was another predictor of acute GVHD with conventional prophylaxis, especially in PBSC recipients [6]. In another large study, the use of PBSC compared to bone marrow (BM) was the risk factor for both acute and chronic GVHD [7].
The Center for International Blood and Marrow Transplant Research (CIBMTR) study with data from 226 centers has identifi ed total body irradiation PBSC, ethnicity, poor performance study and positive cytomegalovirus status of donor and recipient as the signifi cant risk factors of acute GVHD [7]. Th e study also showed that ABO incompatibility was not a signifi cant factor, and the incidence of GVHD in CML is higher probably due to transplantation techniques.
The abovementioned studies were conducted relatively long ago, and were based on population of patients receiving predominantly cyclosporine and methotrexate (MTX) as prophylaxis, and ATG in unrelated donors. However, transplantation technologies have signifi cantly evolved over time. Novel prophylaxis regimens have been introduced, like mTOR inhibitors [8], posttransplant cyclophosphamide (PTCy) [9], TCR alpha/beta cell depletion [10]. No studies have been published on risk factors of GVHD with these novel approaches. In the present study, we searched for risk factors in two large cohorts of patients, one with conventional prophylaxis based on calcineurin inhibitors (CNIs) with MTX/mycophenolate mofetil (MMF) and other, with PTCy prophylaxis. Th e purpose of this study was to evaluate whether GVHD prophylaxis does change the pattern of risk
factors.
Patients and methods
One thousand thirteen adult patients transplanted at the First State I. Pavlov Medical University from 2006 to 2017 were included into the study. All the patients were graft ed either from matched related donor (32%) or unrelated donor (68%). In this group, 470 patients received prophylaxis with PTCy, and 543 were subjected to conventional prophylaxis (Table 1). Only patients who successfully engraft ed were included in the analysis.
GVHD prophylaxis under conventional regimen included tacrolimus with target concentration of 5 to 15 ng/ml, starting from day-1 until day+120, or cyclosporine A with target concentrations of 150 to 350 ng/ml, starting from day-1 until day+120. Th e second agent was either MMF 30 mg/kg (day -1 to day+30), or methotrexate 15 mg/m2 (day+1, 10 mg/m2; day +3, 6). Th e recipients of unrelated graft s did also receive ATG (ATGAM, Pfi zer, Inc.), at 20 mg/kg from day -3 until day -1. In the PTCy group, the prophylaxis consisted of single-agent cyclophosphamide (50 mg/kg) on days +3,+4 for matched related or unrelated bone marrow. In recipients of PBSCs, we used cyclophosphamide (50 mg/kg) on days +3,+4 followed by tacrolimus and MMF (30mg/kg) starting on day +5. In the mismatched graft s, the dose of MMF was increased to 45 mg/kg. Myeloablative conditioning (MAC) in conventional prophylaxis group was performed with oral busulfan (16 mg/kg), and cyclophosphamide (120 mg/kg). In the PTCy group, the majority of patients received MAC containing fl udarabine 180 mg/m2 and busulfan 14 mg/kg. Reduced-intensity conditioning (RIC) was performed with oral busulfan (8 mg/kg) and fl udarabine (180 mg/m2). Minority of patients received conditioning with melphalan (140 mg/m2) and fl udarabine (150 mg/m2. RIC was performed in patients, who were either older than 40 years, had HSCT-specifi c co-morbidity index (HCT-CI)≥2, or exhibited, at least, grade 3 hepatotoxicity during the induction therapy. Supportive care did not diff er for the two prophylaxis arms.
Statistical analysis
Th e Consensus Conference criteria were used for acute GVHD grading [11] and National Institutes of Health criteria were used for chronic GVHD grading [12]. Diagnosis of skin GVHD was established either clinically or histologically, the diagnosis of liver GVHD was assessed clinically, whereas gastrointestinal GVHD was specifi ed by pathological examination. Incidence of acute and chronic GVHD was evaluated with cumulative incidence estimates. Time frame for acute GVHD was 125 days, for chronic GVHD, 2 years. Evaluation of risk factors was performed by means of Gray test. Early discontinuation of immunosuppression due to relapse or minimal residual disease was considered a competing risk for aGVHD. Donor lymphocyte infusion was considered a competing risk for cGVHD. Multivariate evaluation and analysis of continuous variables were done using Fine and Grey regression. Th e variables were selected for the multivariate analysis in case of signifi cance <0.15 obtained in the univariate mode. Th e cutoff levels for continuous variables were determined in ROC analysis with maximal sum of sensitivity and specifi city as a criterion. Th e analyses were conducted in SAS 9.3 (SAS Institute, Inc.).
Results
The conventional prophylaxis group comprised 199 recipients of matched related graft s and 344 subjects were transplanted from unrelated donors. The PTCy group consisted of 104 matched related transplants, and 27 matched unrelated HSCTs, with single-agent PTCy prophylaxis. 338 patients received combined prophylaxis with PTCy, tacrolimus and MMF. Among the evaluated patients, 93.4% has engraft ed. Among the engraft ed patients, 436 received PTCy prophylaxis and 485, conventional GVHD prophylaxis, with a fi veyear survival of 47%. Incidence of acute GVHD in the whole group was 43.9%. Of them, 18.6% had grade I; 9.8%, grade II; 12.6%, grade III, and 3% had grade IV GVHD. Th e incidence of chronic GVHD was 31.6%, including 12.6% with mild; 9%, moderate degree, and 10% showed severe GVHD according to NIH criteria. Th e most common organs involved in chronic GVHD were skin, mucosa, eyes, gastrointestinal tract (GIT) and liver (Fig. 1). Incidence of acute GVHD in the PTCy group was 35%; grade II-IV acute GVHD, 15%; chronic GVHD, 29%. Moderate and severe chronic GVHD was registered in 18% of the cases. Similar incidence rates (resp., 53%, 35%, 35% and 30%) were noted for conventional prophylaxis.
Table 1. Patients’ characteristics in the study group
AML= acute myeloblastic leukemia; ALL =acute lymphoblastic leukemia; CML= chronic myeloid leukemia; HL= Hodgkin lymphoma; MDS= myelodysplastic syndrome; АА=aplastic anemia; NHL=non-Hodgkin lymphoma MF=myelofi brosis; MPN=myeloproliferative neoplasm; CLL=chronic lymphoid leukemia; MAC=myeloablative regimen; RIC =reduced-intensity conditioning.
Figure 1. The incidence and severity of acute (A) and chronic GVHD (B). The incidence of organ involvement is calculated only for the patients who developed GVHD
Figure 2. Risk factors of acute GVHD grade II-IV after conventional prophylaxis (A) and posttransplant cyclophosphamide (B). Number of CD34+ cells in the graft, age and BMI are continuous variables, all the others are logistic
For the conventional prophylaxis group, the following factors were revealed in the univariate analysis with signifi cance >0.15 for acute GVHD grade II-IV development: unrelated donor (p<0.0001), salvage group (p=0.0014), number of HSCT (p=0.1064), ABO incompatibility (p=0.0709), cytomegalovirus (CMV) serostatus (p=0.1487), graft source (p=0.0004 conditioning intensity (p=0.0003), alkylating agents in the conditioning (0.1377), age of the recipient (0.0002), CD34 cell number in the graft (p<0.0001), engraft - ment time (p<0.0001), diagnosis (p=0.0379), body mass index (BMI) (p=0.0220). Th ese parameters were included into the multivariate model where only unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96-0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and engraft ment before day +15 (HR 1.55, 95%CI 1.08-2.22) signifi cantly affected the incidence of acute GVHD grade II-IV (Figure 2A). Th e BMI cut-off value was 28 kg/m2 indicating that obese patients had less acute GVHD. Despite common risk factor of graft source, the fast engraft ment was more signifi cant than the graft source factor (p=0.48), despite the fact that fast engraft ment occurred more oft en in the PBSC recipients (32% vs 17%, p<0.0001).
In the univariate analysis of PTCy group, only unrelated donor (p=0.0170), HLA matching (p=0.0347), number of HSCT (p=0.0592), recipient gender (p=0.0592), CMV serostatus (p=0.0592), female donor for male recipient (p=0.0706), time of engraft ment (p=0.0037), and time from diagnosis to transplant were shown to be signifi cant factors (p<0.0001). Since the recipient gender was signifi cant because of female-male combination, only that factor was included in the multivariate analysis. Also in ROC analysis, the cut-off for engraft ment time was diff erent: 20 days instead of 15. Th ese parameters were added to the multivariate model where CMV serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Th e highest incidence was in the -/- pair of donor / recipient (32%), lower in the +/- pair (20%) and the lowest in the CMV-positive recipients (13% with +/+ pair vs 15% with -/+ pair). Th e univariate analysis in conventional prophylaxis group revealed unrelated donor (p=0.0002), salvage group (p=0.0635), cytomegalovirus serostatus (p=0.0248), graft source (p<0.0001), age (p=0.1360), number of CD34 cells in the graft (p=0.0047), engraft ment at <15 days (p=0.0013), time from diagnosis to transplantation (p=0.1151), diagnosis (p=0.0205) and previous acute GVHD (p<.0001) as signifi cant factors for moderate and severe chronic GVHD. In the PTCy group, the univariate analysis revealed unrelated donor (p=0.0980), donor gender (p=0.0138), graft source (p=0.0805), male recipient with female donor (p=0.1082), number of CD34+ cells in the graft (p=0.0272), time to engraft ment (p=0.0302) and previous acute GVHD (p=0.0929), as predisposing factors for chronic GVHD. In the multivariate model with conventional GVHD prophylaxis, only PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37) were signifi cant risk factors for moderate and severe chronic GVHD (Figure 3A).
Figure 3. Risk factors for moderate and severe chronic GVHD with conventional prophylaxis (A) and posttransplantation cyclophosphamide (B)
Modeling in the PTCy group demonstrated only a weak statistical signifi cance for previous acute GVHD (HR 1.59, 95%CI 0.99-2.54), while all the other factors were non-significant (Figure 3B).
Regarding mild acute GVHD (grade I-II) which is usually favorable for prognosis in the conventional prophylaxis group, only the CD34 cell dose increased the probability of this condition (HR 1.08, 95%CI 1.01-1.150, р=0.0133). The other variables were not signifi cantly different. With PTCy prophylaxis, the unrelated donorship was associated with increased probability of grade I-II acute GVHD (HR 3.26, 95%CI 1.26-8.39, p=0.0145). Also a combination of a female donor/ male recipient had week statistical signifi cance (HR 1.87, 0.94-3.72, p=0.0761). No predictors were determined for mild chronic GVHD in conventional prophylaxis patients, whereas, with PTCy, the CMV-positive recipient serostatus was protective against this condition (HR 0.675, 0.496-0.918, p=0.0123). Mild chronic GVHD was lowest in +/+ CMV positive donor/ recipient (6%), being highest in -/+ (15%) and +/- (19%) combinations. In the both CMV-negative pairs, mild chronic GVHD rate was also substantial (14%).
Discussion
In this relatively large study, we have confi rmed that the novel prophylaxis regimens may dramatically change the landscape of risk factors which was not demonstrated before. Previous registry studies mostly documented only evolutional changes in the risk factors due to other aspects of HSCT. In the era of only BM transplantation from matched siblings with cyclosporine and methotrexate as prophylaxis, the predominant risk factors were female donor for male recipient, pregnancy history and older recipient age [13]. Th e subsequent CIBMTR study identifi ed the risk factors of PBSC use, ethnicity, TBI versus busulfan-based conditioning, and positive CMV serostatus [7]. Aft er broad introduction of unrelated transplants, it became obvious that GVHD incidence is higher than aft er sibling transplants [14]. Additional risks of GVHD are associated with partial HLA mismatches [15] and non-HLA allele mismatches [16]. Furthermore, the donor age was also identifi ed as risk factor in unrelated HSCT [17]. Nonetheless the recent mathematical analysis indicates that the predictive potential of clinical parameters is relatively low [18]. Thus, the risk factors of GVHD were slowly evolving, due to implementation of novel cell sources and donor types. We, however, confi rm that the use of PTCy completely abolished the previously signifi cant risk factors. It has been previously published that HLA matching is not a signifi cant factor with PTCy prophylaxis [19], and this was confirmed in the current study. Nonetheless, the diff erence between matched sibling and unrelated donor had a tendency to signifi cance, which was also confirmed in our group of patients. What was not established earlier is the preventive
role of CMV-positive serology in recipient, despite a weak statistical trend in the EBMT study [20]. Th e probable reason for that is diff erent prevalence of CMV seropositivity in Russia, Europe and the USA. In Russia, the CMV seroprevalence is above 85% [21, 22, 23]. Th e CMV seropositivity is unlikely to represent the reason for diff erences, but, rather, it may be a consequence of changes in immune system that, probably, led to decreased GVHD incidence. It was demonstrated that CMV causes expansion of T-regulatory cells [24] and upregulation of IL-33 pathway, which protects against lethal GVHD in animal models [25, 26]. Th e signifi cance of this factor with no such evidence for conventional prophylaxis [7] indicates the presence of different immunological mechanisms behind PTCy prophylaxis that still should be elucidated.
The risk factors identifi ed for moderate and severe chronic GVHD with conventional prophylaxis were similar to the ones previously reported [27, 28]. Th e history of severe acute GVHD was the most predominant risk factor. However, no risk factors were identifi ed for PTCy, probably due to low incidence of this complication and low incidence of preceding acute GVHD in the study cohort. Contrary to this data, the European Registry Study defi ned recipient age, use of PBSC and combination prophylaxis as the risk factors [20]. Th e diff erences might be due to diff erent PTCy schedule (day +3, +5), use of cyclosporine instead of tacrolimus, duration
of immunosuppression [29]. Th e absence of diff erences between PBSC and BM is explained by single-agent PTCy prophylaxis in the matched bone marrow group and combination with tacrolimus and MMF in the PBSC group, which alleviated the diff erences.
In conclusion, this study identified the changing pattern of GVHD risk factors with introduction of novel prophylaxis regimens in related and unrelated HSCT graft s. Further studies are required to elucidate the biological mechanisms behind these changes.
Conflicts of interest
No conflicts of interest are reported by the authors.
References
1. Passweg JR, Baldomero H, Bader P, Basak GW, Bonini C, Duarte R, Dufour C, Kroeger N, Kuball J, Lankester A, Montoto S, Nagler A, Snowden JA, Styczynski J, Mohty M. Is the use of unrelated donor transplantation leveling off in Europe? Th e 2016 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2018. doi: 10.1038/s41409-018-0153-1 [Epub ahead of print].
2. D'Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR summary slides, 2017. Available at: www.cibmtr.org, as of 28/07/18.
3. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, Sanders JE, Witherspoon RP, Storb R, Appelbaum FR, Martin PJ. Th erapy for chronic graft -versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood. 2002;100(1):48-51.
4. Saliba RM, Couriel DR, Giralt S, Rondon G, Okoroji GJ, Rashid A, Champlin RE, Alousi AM. Prognostic value of response aft er upfront therapy for acute GVHD. Bone Marrow Transplant. 2012;47(1):125-131.
5. Flowers ME, Inamoto Y, Carpenter PA, Lee SJ, Kiem HP, Petersdorf EW, Pereira SE, Nash RA, Mielcarek M, Fero ML, Warren EH, Sanders JE, Storb RF, Appelbaum FR, Storer BE, Martin PJ. Comparative analysis of risk factors for acute graft -versus-host disease and for chronic graft -versus-host disease according to National Institutes of Health consensus criteria. Blood. 2011;117(11):3214-3219.
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В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. 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array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20866" ["VALUE"]=> array(2) { ["TEXT"]=> string(309) "Иван С. Моисеев, Елена И. Дарская, Татьяна А. Быкова, Александр Л. Алянский, Елена В. Бабенко, Елена В. Морозова, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(303) "Иван С. Моисеев, Елена И. Дарская, Татьяна А. Быкова, Александр Л. Алянский, Елена В. Бабенко, Елена В. Морозова, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20867" ["VALUE"]=> array(2) { ["TEXT"]=> string(348) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(342) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20868" ["VALUE"]=> array(2) { ["TEXT"]=> string(4047) "<p style="text-align: justify;"> Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3981) "
Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.
Ключевые слова
Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20872" ["VALUE"]=> array(2) { ["TEXT"]=> string(2158) "<p style="text-align: justify;"> Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2092) "
Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.
Keywords
Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.
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Moiseev, Elena I. Darskaya, Tatyana A. Bykova, Elena V. Morozova, Alexander L. Alyanskiy, Elena V. Babenko, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(177) "Ivan S. Moiseev, Elena I. Darskaya, Tatyana A. Bykova, Elena V. Morozova, Alexander L. Alyanskiy, Elena V. Babenko, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(177) "Ivan S. Moiseev, Elena I. Darskaya, Tatyana A. Bykova, Elena V. Morozova, Alexander L. Alyanskiy, Elena V. Babenko, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20872" ["VALUE"]=> array(2) { ["TEXT"]=> string(2158) "<p style="text-align: justify;"> Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2092) "
Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.
Keywords
Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2092) "Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.
Keywords
Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(303) "Иван С. Моисеев, Елена И. Дарская, Татьяна А. Быкова, Александр Л. Алянский, Елена В. Бабенко, Елена В. Морозова, Сергей Н. Бондаренко, Инна В. Маркова, Борис В. Афанасьев
" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20868" ["VALUE"]=> array(2) { ["TEXT"]=> string(4047) "<p style="text-align: justify;"> Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3981) "
Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.
Ключевые слова
Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3981) "Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.
Ключевые слова
Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.
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Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is eff ective method of treatment for malignancies, some solid tumors and hereditary diseases in children and adults [1]. Th e main success factors are dependent on the underlying disease status at the time of therapy initiation, and the level of HLA-match between recipient and donor of hematopoietic stem cells which is a key factor to increase the chance for engraft ment, and to reduce development of acute and chronic graft -versus-host disease (GvHD) [2].
Since the beginning of allo-HSCT implementation as a treatment method from the middle of the XX century, there is a great progress in accessibility and safety of this treatment approach. However, ABO- and Rhesus-incompatibility between patient and donor in allo-HSCT are shown in 30-50% of cases, thus leading to additional complications and erythrocyte recovery delay [3, 4]. The presence of ABO-incompatibility requires higher level of immunological security measures while providing replacement transfusion therapy: compliance with ABO-compatibility rules, depending on the level of posttransplant chimerism; X- or γ-irradiation of erythrocyte and platelet-containing blood products before transfusion, leukofi ltration technology [5].
There are three ABO-incompatibility types – minor (20-25% of all cases), major (20-25%) and bidirectional (5%) (Table 1) [6].
ABO-incompatibility may predispose for some severe complications, such as acute and delayed hemolysis, pure red cell aplasia (PRCA) [7], GvHD [8], graft failure [9], autoimmune hemolytic anemia [10], which negatively aff ect the eff ectiveness of HSCT by increasing mortality [11]. At the same time, there are studies which yield confl icting results and do not reveal distinct impact of ABO mismatch upon the treatment outcomes [8, 12, 13]. Data ambivalence of ABO- and Rhesus-incompatibility impact in allo-HSCT, determined a rationale of a large cohort study, which would allow of creating more homogeneous comparison groups by the main parameters, and, therefore, increase the signifi cance of results. The aim of our study was to specify the role of ABO-incompatibility in allo-HSCT for a well-characterized cohort of patients.
Patients and methods
From 1999 to 2015, 1132 patients with malignancies and hereditary diseases undergone 1482 allo-HSCT at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation (Tab. 2). 149 patients have received second graft , 13 of them – triple (in most cases, from the same donor).
Patients with acute myeloid leukemia (n=568), acute lymphoblastic leukemia (n=475), chronic myeloid leukemia (n=94), myelodysplastic syndrome (n=76), severe aplastic anemia (n=57) represented the dominant clinical group. Over recent years, an increased allo-HSCT activity has been registered for orphan diseases (n=49) and solid tumors in children (n=9).
The choice of conditioning regimen was determined by diagnosis, disease status and patient somatic state. Myeloablative conditioning regimen (MAC) was used in 431 patients (29.5%), non-myeloablative regimens (RIC), were applied in 1030 cases (70.5%). Busulfan + cyclophosphamide drug combination (n=301) was the most frequently used protocol (69.8% of total MAC-treated group). RIC regimens, i.e., busulfan+ fl udarabine, or melphalan+ fludarabine were used, respectively, in 515 (50%) and 21% (n=217).
GvHD prophylaxis was carried out in accordance with European Group for Bone Marrow Transplantation (EBMT) Recommendations, R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation policies, and include cyclophosphamide alone or combinations of immunosuppressive drugs: cyclosporine A, tacrolimus, sirolimus, with their pharmacokinetic control in serum; also combined with methotrexate, mycophenolate mofetil, antithymocyte globulin (ATG).
Evaluation engraft ment and staging of posttransplant complications were made according to standard defi nitions and classifi cations [14-17], and EBMT 2012 Recommendations. Th e fi rst detection of donor RBC in two or more consecutive peripheral blood tests by serological methods was considered to be the beginning of donor chimerism [18].
Standard laboratory techniques for ABO, Rh (D, C, c, E, e, K, Cw) and Cellano (Kell) evaluation were used: cross-method with monoclonal antibodies and micro-typing system (IDcard, Bio Rad). Direct antiglobulin test was made by standard gel method (ID Liss Coombs, DC-Screening I, Bio Rad Laboratories).
In order to reduce the risk of immune transfusion reactions in case of ABO-incompatibility, graft manipulation technologies were used: in case of major ABO-incompatibility, removal of incompatible donor erythrocytes (sedimentation with 6% hydroxyethyl starch); in case of minor incompatibility, donor plasma was removed by centrifugation procedure; in case of bidirectional mismatch, a combination of the methods was used.
Table 1. Different types of donor/recipient ABO incompatibility in allogeneic HSCT [6]
Table 2. Allo-HSCT recipient’s characteristics
If necessary, blood transfusion therapy was carried out according to ABO-status and general recommendations [6]. Statistical analysis was performed using IBM SPSS Statistics version 13.0 by the rules and international recommendations for processing and providing the results of HSCT [19] and include following statistical methods: descriptive statistics for quantitative variables, parametric statistics, description of nominal variables (ABO-incompatibility impact assessment on the development of GvHD); overall survival (OS) analysis was performed by Kaplan-Mayer method using logrank test. To reveal the factors associated with engraft ment terms, a logarithmic utility function (logworth) was used. Th e role of various factors infl uencing posttransplant period and chimerism development was assessed by multivariate analysis (Cox regression). The difference between individual indicators was considered statistically signifi cant at p<0.05.
Results
Impact of ABO blood groups and Rhesus factor on the allo-HSCT effectiveness
In the present study, comprehensive analysis on the impact of ABO- and Rhesus-incompatibility on allo-HSCT effi ciency and risk of complications was performed. Patient's ABO blood group, as an independent parameter, did not aff ect 1-year OS in patients with malignant diseases in allo-HSCT (n=1366), p=0.48. At the same time, negative (n=186) or positive (n=1180) Rhesus factor in the patients proved to be a valuable predictive marker, since its negative status aff ected 1-year OS in allo-HSCT – 48%, with respective average value of 8.1 months, (HR 0.324; 95% CI 7.553 – 8.822), and 59% (average – 8.8 months, HR 0.126; 95% CI 8.605 – 9.101), being signifi cantly diff erent at p=0.01 (Fig. 1).
Rhesus system antigens have a much lower degree of immunogenicity compared to potential eff ects of ABO system, but it can contribute to allo-sensibilisation and promotion of hemolytic complications, thereby reducing the effi ciency of allo-HSCT, which was confi rmed in this study. When comparing pre-transplant RBC phenotypes in the patients with malignancies (n=1175), the following combinations have been found to aff ect the one-year OS (Fig. 2):
- DCCee (n=197) vs ddccee (n=157), 65% (mean, 9.5 months; HR 0.283; 95% CI 8.945-10.056) and 50% (median, 11.4 months; HR 0.348; 95% CI 7.706-9.069), respectively, p=0.006;
- Dccee (n=450) vs ddccee (n=157), 63% (mean – 9 months, HR 0.198; 95% CI 8.672-9.45) and 50%, respectively, p=0.025.
Studying clinical eff ects and outcomes depending on the Rh antigen status of the donor (n=998) confi rm the assumption of a more pronounced negative eff ects of homozygous and D-negative Rh phenotypes upon overall patient survival (Fig. 3):
- DCcEe (n=124) vs DCcee (n=389), 67% and 58%, respectively, (χ2 – 5.454) p=0.019;
- DCcEe (n=124) vs ddccee (n=158), 67% and 53%, respectively, (χ2 – 5.985) p=0.014.
Thus, presence of negative Rhesus factor in the patients (p=0.01) corresponding to the ddccee phenotype (p=0.006), and negative Rhesus factor in graft donor (ddccee phenotype, p=0.014), is associated with a decrease in 1-year OS in patients with malignant diseases, compared with patient’s positive Rhesus and phenotypes DCCee, Dccee and graft donor’s phenotype DCcEe, respectively.
Figure 1. One-year OS in patients with malignant diseases after allo-HSCT depending on the patient’s Rh status
Figure 2. One-year OS in patients with malignant diseases after allo-HSCT, depending on the patient’s erythrocytes Rh phenotype
Figure 3. One-year OS in patients after allo-HSCT, depending on graft donor’s erythrocyte phenotype
The impact of ABO-mismatches on OS and the risk of GvHD development in allo-HSCT
In our study, ABO-incompatibility (n=1428) was documented in 54.6% of allo-HSCT cases (n=780), with major or minor mismatch shown, respectively in 37.8% (n=295), and 45.4% of the cases (n=354); and bidirectional incompatibility having been registered in 16.8% of the cohort (n=131), which is slightly more frequent compared to the worldwide data [4], due to specifi c variability of the gene polymorphisms in the multinational population of Russian Federation, and a significant number of graft s from the foreign unrelated donors used at our HSCT Center.
Th e authors opinion and literature data on the impact of ABO-incompatibility on OS are contradictory since most of them did not prove a negative infl uence upon HSCT outcome. However, the 10-year experience of French BMT group (n=1108) indicate to a negative impact of minor ABO-incompatibility in allo-HSCT patients treated with RIC combination with fl udarabine and low-dose total body irradiation or fl udarabine and busulfan with rabbit ATG, along with absence of remission, and inclusion of ATG>10mg/kg into the GvHD prophylaxys schemes [20].
According to our data, minor ABO-incompatibility in patients with leukemia in remission (n=600) was associated with reduced D+100 OS rates when compared with ABO-compatible allo-HSCT, p=0.05 (Fig. 4): in ABO-compatible patient/donor HSCT, 91% (n=262, a mean of 95 days, HR 0.998; 95% CI 93.32-97.23); for major ABO-incompatibility, 85% (n=117, a mean of 92 days, HR 1.809; 95% CI 89.088-96.179); for minor ABO mismatches, 85% (n=163, an average value of 92 days, HR 1.527; 95% CI 89.324-95.309), and for bidirectional incoompatibility, 93% (n=58, average level of 95 days, HR 1.703; 95% CI 93.207-99.883), respectively. Further analysis was performed according to the type of ABO-incompatibility in combination with conditioning regimens, GvHD prophylaxis, taking into account diff erent degree of myeloablation, mechanisms of immunosuppression and possible risk potentiation for immune complications. A combination of MAC and major ABO-incompatibility in patients with leukemia in remission (n=215) was found to be associated with a decreased OS at 100-days aft er allo- HSCT, if compared with ABO-compatible allo-HSCT, p=0.025 (Fig. 5) which should be taken into account when choosing the conditioning treatment mode. I.e., the OS value for ABO-compatible patients (n=103) was 91% (average of 95 days, HR 1.598; 95% CI 91.885-98.148), in the pairs with major ABO-incompatibility (n=37), the OS value was 76% (average, 88 days, HR 3.765; 95% CI 80.95-95.709). The 100-d OS in cases of minor ABO mismatch (n=56) was 82% (average, 91 days, HR 2.762; 95% CI 86.039-96.868); for bidirectional incompatibility, (n=19), the OS was 89% (average, 93 days, HR 4.364; 95% CI 84.831-101.937).
Figure 4. OS rates for the D+100, depending on the type of ABO-incompatibility in patients with leukemia in remission with allo-HSCT
Figure 5. OS rates on D+100 depending on the type of ABO-incompatibility and MAC in patients with leukemia in remission
Discussion
A high risk for ABO-incompatibility is an additional factor potentiating immunological reactivity, thus increasing risk of GvHD and possible hemolytic complications remains controversial. A number of publications noted higher frequency of acute GvHD grade III-IV in the case of major and minor ABO-incompatibility [21]. On the other hand, a group of scientists from Seattle presented data from the large US National Bone Marrow Donor Program showing no signifi cant diff erence in the development of acute GvHD depending on the ABO-incompatibility type [22].
Results of our study indicate that the type of ABO-incompatibility: major (n=123), minor (n=167) or bidirectional (n=61) did not increase either severity, or incidence of acute GvHD (grade I-IV) in patients with leukemia transplanted in remission (n=626), compared to ABO-compatible HSCT (n=275), p=0.85. Acute GvHD developed in ABO-compatible HSCT in 52% of cases (n=143), in major ABO-incompatibility, 48.8% (n=60), in minor ABO-mismatch, 50.9% (n=85), in bidirectional mismatch, 55.7% (n=34), respectively.
Likewise, the type of ABO-incompatibility: major (n=123), minor (n=167), bidirectional (n=61); did not increase the risk of chronic GvHD in patients with leukemia treated in remission (n=626) compared to ABO-compatible HSCT (n=275), p=0.21. Chronic GvHD developed in ABO-compatible HSCT in 26.5% of cases (n=73); in major ABO-incompatibility, 24.4% of cases (n=30); in minor, 24% of cases (n=40); in bidirectional, 37.7% (n=23), respectively.
The impact of ABO-incompatibility on engraftment
According to the results of our study, in general cohort of patients with allo-HSCT, the leukocyte recovery >1.0x109/l was observed on day 18 (mean ± standard deviation – 20±10.4); neutrophil recovery >0.5x109/l – on day 17 (20.5±13.6); platelet recovery >20x109/l – on day 14 (21±17.8); platelet recovery >50x109/l – on day 16 (23.2±15). Th e most significant factors which determined time of engraft ment were as follows: HLA–match (logworth, 15.1), graft source (logworth, 7.05), type of allo-HSCT (logworth 6.4), conditioning regimen (logworth, 4.05). Th e factors which increased the engraft ment time were as follows: 9/10 HLA-match, MAC regimen, bone marrow as a source of transplant. In turn, ABO- and Rhesus-incompatibility had a much smaller impact on neutrophils and platelets engraft ment timeline: ABO-incompatibility (logworth of 0.87), blood group of the donor (logworth, 0.34), patient’s erythrocyte phenotype (logworth, 0.33), donor’s Rhesus factor (logworth, 0.27), donor’s erythrocyte phenotype (logworth, 0.001).
However, as exemplifi ed by 240 recipients of allo-HSCT, the diff erences in recovery time of erythrocyte counts on D+50 proved to be dependent on ABO-incompatibility, i.e., the patients from ABO-compatible donor/patient pairs achieved RBC recovery in 23.8% of cases, and those with ABO-incompatibility, in 10% (p=0.01).
Th e results of this study suggest that the 100% donor chimerism for ABO blood groups was reached in 159 of 240 patients (17 to 229 days, a median of 84 days). In 81 patients, the results could not be assessed due to their death in early posttransplant period (n=50); inability to identify diff erences, due to identity for ABO-, Rhesus-system (D, C, c, E, e) and Kell markers (n=7); lack of laboratory data due to incomplete patient's data obtained posttransplant (n=24). Primary diagnosis (p=0.87), disease status (p=0.69), allo- HSCT type (p=0.26), graft source (p=0.28), degree of HLA match (p=0.62) and conditioning regimens (p=0.39) did not have a negative impact on blood group conversion terms. ABO-incompatibility was the only identifi ed factor increasing chimerism time development (p=0.0001).
For ABO-compatible allo-HSCT with Rh incompatibility (n=52), the time to achieve 100% chimerism was 95±44 days (31-226 days, HR 6,106; 95% CI 82.9-107.4), with major ABO-incompatibility (n=29) – 109±51 days (27-229 days, HR 9.642; 95% CI 89.9-129.4), with minor (n=57) – 67±22 days (17-109 days, HR 3,032; 95% CI 61-73,1), with bidirectional mismatches (n=21) – 72±16 days (48-117 days, HR
3,515; 95% CI 65,3-80).
Negative effect of ABO-incompatibility type on erythroid time recovery, is refl ected in posttransplant transfusion therapy intensiveness (p=0,003). Th e average number of transfusions of blood components was 25 units in major ABO-incompatibility (p=0.001); 16.5, in minor mismatch (p=0.006); 13.6, in bidirectional (p=0.005); 15.1, in ABO-compatible allo-HSCT (p=0.001), respectively.
HSCT complications associated with ABO-incompatibility
Additional attention is paid to the development of specifi c complications associated with ABO-incompatibility. Clinical manifestations in this case may be due to localization of ABO system antigens, which are represented not only on erythrocytes, but also on other cells and tissues: platelets, lymphocytes, endothelium of blood vessels and organs (kidneys, liver, heart) circulating in plasma [23].
According to our data, the risk of immune complications in allo-HCT (n=1158) is 2.8% (n=33) versus 4.1% in the presence of ABO-incompatibility (n=638, p=0.02), as seen from Table 3. A low number of cases and mortality (n=3) may indicate adequate prevention, timely and eff ective treatment.
Design of OS predictive models in allo-HSCT
One of the main objectives in multivariate analysis was to identify factors and their combinations that aff ect OS in allo-HSCT, and to create a mathematical model for predicting the probability of potential complications, which will allow for timely prophylaxis and treatment. The study was based on Cox regression with preliminary exploratory analysis for patients with malignant diseases, which was performed as a Kaplan-Meier test for nominal variables-factors aff ecting the outcome of treatment [24]. As a result of the analysis, the following predictors aff ecting OS were identified: degree of HLA-match, presence of acute GvHD, major ABO-incompatibility, allo-HSCT type, status of the underlying disease, and use of ATG for GvHD prophylaxis (Fig. 6).
Our valid predictive model of 100-day OS may serve such an example, which included patients with leukaemia (n=140) from 9/10 HLA-matched related and unrelated donor, in case of engraft ment up to D+31 (Fig. 7).
Figure 6. OS predictors in allo-HSCT patients with malignant diseases
Figure 7. 100-day OS predictive model in patients with allo-HSCT with 9/10 HLA-match with engraftment up to D+31
Note: Profile 1: MAC, major ABO-incompatibility, GvHD prophylaxis – cyclophosphamide containing schemes; Profi le 2: MAC, major ABO-incompatibility, GvHD prophylaxis «cyclosporine A + methotrexate» or « tacrolimus + methotrexate». Table 3. Development of immune complications in allo-HSCT depending on the ABO-incompatibility type
Table 3. Development of immune complications in allo-HSCT depending on the ABO-incompatibility type
Conclusion
The data presented in this study suggest that ABO-incompatibility may be a negative factor reducing eff ectiveness of treatment in allo-HSCT, especially in the early posttransplantation period and during the fi rst year posttransplant. Adverse eff ects of ABO-incompatibility are realized through allosensitization, increasing the frequency of hemolytic complications and delaying erythroid recovery.
It seems that the main tool for minimizing the ABO-incompatibility consequences is the donor graft preparation based on ABO-incompatibility type, which allows achieving low frequency and severity of possible hemolytic complications.
The next factor of important value is the replacement transfusion therapy, which should be based on red blood cells chimerism level and comply with the principles to use the most leukocyte depleted blood components, which can improve the efficiency of blood transfusions and reduce the risk of posttransfusion reactions and complications.
Thus, when choosing an allogeneic bone marrow donor, giving priority to a higher degree of HLA-match and CMV-status in "recipient-donor" pair, it is also optimal to choose, if possible, an ABO- and Rhesus compatible donor.
Conflict of interests
The authors have noconflict of interest to declare.
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3. Rowley SD, Donato ML, Bhattacharyya P. Red blood cell-incompatible allogeneic hematopoietic progenitor cell transplantation. Bone Marrow Transplantation. 2011; 46; 1167-1185.
4. Worel N. ABO-mismatched allogeneic hematopoietic stem cell transplantation. Transfus Med Hemother. 2016; 34:3-12.
5. Sidorkevich SV, Akimova OV, Petrenko GI, Belyakov MV, Martynova MV, Kolesov AA, Chernikova ES, Savicheva IV. Transfusion support in hematopoietic stem cell transplantation in patients with malignancy. Transfusiology. 2014;15(2): 93-94 (In Russian).
6. Booth GS, Gehrie EA, Bolan CD, Savani BN. Clinical guide to ABO-incompatible allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013; 13: 1152-1158.
7. Worel N, Greinix HT, Schneider B, Kurz M, Rabitsch W, Knöbl P, Reiter E, Derfl er K, Fischer G, Hinterberger W, Höcker P, Kalhs P. Regeneration of erythropoiesis aft er related- and unrelated-donor BMT or peripheral blood HPC transplantation: a major ABO mismatch means problems. Transfusion. 2000;40: 543-550.
8. Seebach JD, Stussi G, Passweg JR, Loberiza FR Jr, Gajewski JL, Keating A, Goerner M, Rowlings PA, Tiberghien P, Elfenbein GJ, Gale RP, van Rood JJ, Reddy V, Gluckman E, Bolwell BJ, Klumpp TR, Horowitz MM, Ringdén O, Barrett AJ. ABO blood group barrier in allogeneic bone marrow transplantation revisited. Biol Blood Marrow Transplant. 2005;11:1006-1013.
9. Remberger M, Watz E, Ringden O, Mattsson J, Shanwell A, Wikman A. Major ABO blood group mismatch increases the risk for graft failure aft er unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007; 13:675-682.
10. Ahmed I, Teruya J, Murray-Krezan C, Krance R. Th e incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post fi rst and second hematopoietic stem cell transplant. Pediatr Transplant. 2015;19(4):391-398.
11. Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, Urbano-Ispizua A, Pavletic SZ, Haagenson MD, Zhang MJ, Antin JH, Bolwell BJ, Bredeson C, Cahn JY, Cairo M, Gale RP, Gupta V, Lee SJ, Litzow M, Weisdorf DJ, Horowitz MM, Hahn T. Risk factors for acute GVHD and survival aft er hematopoietic cell transplantation. Blood 2012;119:296-307.
12. Atay D, Erbey F, Akcay A, Ozturk G. Is ABO mismatch another risk factor for allogeneic hematopoietic stem cell transplantation in pediatric thalassemic patients? Pediatr Transplant 2015; 19(6); 645-651.
13. Gutiérrez-Aguirre CH, Gómez-De-León A, Alatorre-Ricardo J, Cantú‐Rodríguez OG, González‐Llano O, Jaime‐Pérez JC, Mancías‐Guerra C, Flores‐Jiménez JA, Gómez‐Almaguer D. Allogeneic peripheral blood stem cell transplantation using reduced-intensity conditioning in an outpatient setting in ABO-incompatible patients: are survival and graft -versus-host disease diff erent? Transfusion. 2014;54(5):1269-1277.
14. Przepiorka D, Weisdorf D, Martin P. 1994 Consensus Conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825.
15. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health Consensus development project on criteria for clinical trials in chronic graft -versus-host disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2005;11:945-955.
16. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, Kerr H, Stratton P, Duarte RF, McDonald GB, Inamoto Y, Vigorito A, Arai S, Datiles MB, Jacobsohn D, Heller T, Kitko CL, Mitchell SA, Martin PJ, Shulman H, Wu RS, Cutler CS, Vogelsang GB, Lee SJ, Pavletic SZ, Flowers ME. National Institutes of Health Consensus development project on criteria for clinical trials in chronic graft -versus-host disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2015; 21(3): 389-401.
17. The National Hematology Society. Clinical guidelines for the diagnosis and treatment of acute myeloid leukemia in adults. II Congress of Hematologists of Russia 2014 (In Russian).
18. Ortho BioVue System Handbook 2015: 1-37.
19. Szydlo RM. Statistical Evaluation of SCT data, haematopoietic stem cell transplantation. Th e EBMT Handbook, 6th Edition (Eds: Apperley, Carreras, Gluckman, Masszi) // Publ: European School of Haematology 2012: 612-628.
20. Michallet M, Le QH, Mohty M, Prébet T, Nicolini F, Boiron JM, Esperou H, Attal M, Milpied N, Lioure B, Bordigoni P, Yakoub-Agha I,Bourhis JH, Rio B,Deconinck E, Renaud M, Chir Z, Blaise D. Predictive factors for outcomes aft er reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Th érapie Cellulaire. Exp Hematol 2008; 36:535-544.
21. Kimura F, Sato K, Kobayashi S, Ikeda T, Sao H, Okamoto S, Miyamura K, Mori S, Akiyama H, Hirokawa M, Ohto H, Ashida H, Motoyoshi K. Impact of ABO-blood group incompatibility on the outcome of recipients of bone marrow transplants from unrelated donors in the Japan Marrow Donor Program. Haematologica 2008; 93:1686-1693.
22. Goldman J, Liesveld J, Nichols D, Heal J, Blumberg N. ABO incompatibility between donor and recipient and clinical outcomes in allogeneic stem cell transplantation. Leuk Res. 2003;27: 489-491.
23. Gehrie EA, Cates JM, Nian H, Olson SJ, Young PP. Blood group A antigen expression on cardiac endothelium is highly individualized: Possible implications for transplantation. Cardiovasc Pathol 2013; 22:251-256.
24. Kleinbaum DG, Klein M. Survival Analysis. A Self-Learning Text. Second Edition, Springer Science & Business Media, Inc 2005.
Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is eff ective method of treatment for malignancies, some solid tumors and hereditary diseases in children and adults [1]. Th e main success factors are dependent on the underlying disease status at the time of therapy initiation, and the level of HLA-match between recipient and donor of hematopoietic stem cells which is a key factor to increase the chance for engraft ment, and to reduce development of acute and chronic graft -versus-host disease (GvHD) [2].
Since the beginning of allo-HSCT implementation as a treatment method from the middle of the XX century, there is a great progress in accessibility and safety of this treatment approach. However, ABO- and Rhesus-incompatibility between patient and donor in allo-HSCT are shown in 30-50% of cases, thus leading to additional complications and erythrocyte recovery delay [3, 4]. The presence of ABO-incompatibility requires higher level of immunological security measures while providing replacement transfusion therapy: compliance with ABO-compatibility rules, depending on the level of posttransplant chimerism; X- or γ-irradiation of erythrocyte and platelet-containing blood products before transfusion, leukofi ltration technology [5].
There are three ABO-incompatibility types – minor (20-25% of all cases), major (20-25%) and bidirectional (5%) (Table 1) [6].
ABO-incompatibility may predispose for some severe complications, such as acute and delayed hemolysis, pure red cell aplasia (PRCA) [7], GvHD [8], graft failure [9], autoimmune hemolytic anemia [10], which negatively aff ect the eff ectiveness of HSCT by increasing mortality [11]. At the same time, there are studies which yield confl icting results and do not reveal distinct impact of ABO mismatch upon the treatment outcomes [8, 12, 13]. Data ambivalence of ABO- and Rhesus-incompatibility impact in allo-HSCT, determined a rationale of a large cohort study, which would allow of creating more homogeneous comparison groups by the main parameters, and, therefore, increase the signifi cance of results. The aim of our study was to specify the role of ABO-incompatibility in allo-HSCT for a well-characterized cohort of patients.
Patients and methods
From 1999 to 2015, 1132 patients with malignancies and hereditary diseases undergone 1482 allo-HSCT at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation (Tab. 2). 149 patients have received second graft , 13 of them – triple (in most cases, from the same donor).
Patients with acute myeloid leukemia (n=568), acute lymphoblastic leukemia (n=475), chronic myeloid leukemia (n=94), myelodysplastic syndrome (n=76), severe aplastic anemia (n=57) represented the dominant clinical group. Over recent years, an increased allo-HSCT activity has been registered for orphan diseases (n=49) and solid tumors in children (n=9).
The choice of conditioning regimen was determined by diagnosis, disease status and patient somatic state. Myeloablative conditioning regimen (MAC) was used in 431 patients (29.5%), non-myeloablative regimens (RIC), were applied in 1030 cases (70.5%). Busulfan + cyclophosphamide drug combination (n=301) was the most frequently used protocol (69.8% of total MAC-treated group). RIC regimens, i.e., busulfan+ fl udarabine, or melphalan+ fludarabine were used, respectively, in 515 (50%) and 21% (n=217).
GvHD prophylaxis was carried out in accordance with European Group for Bone Marrow Transplantation (EBMT) Recommendations, R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation policies, and include cyclophosphamide alone or combinations of immunosuppressive drugs: cyclosporine A, tacrolimus, sirolimus, with their pharmacokinetic control in serum; also combined with methotrexate, mycophenolate mofetil, antithymocyte globulin (ATG).
Evaluation engraft ment and staging of posttransplant complications were made according to standard defi nitions and classifi cations [14-17], and EBMT 2012 Recommendations. Th e fi rst detection of donor RBC in two or more consecutive peripheral blood tests by serological methods was considered to be the beginning of donor chimerism [18].
Standard laboratory techniques for ABO, Rh (D, C, c, E, e, K, Cw) and Cellano (Kell) evaluation were used: cross-method with monoclonal antibodies and micro-typing system (IDcard, Bio Rad). Direct antiglobulin test was made by standard gel method (ID Liss Coombs, DC-Screening I, Bio Rad Laboratories).
In order to reduce the risk of immune transfusion reactions in case of ABO-incompatibility, graft manipulation technologies were used: in case of major ABO-incompatibility, removal of incompatible donor erythrocytes (sedimentation with 6% hydroxyethyl starch); in case of minor incompatibility, donor plasma was removed by centrifugation procedure; in case of bidirectional mismatch, a combination of the methods was used.
Table 1. Different types of donor/recipient ABO incompatibility in allogeneic HSCT [6]
Table 2. Allo-HSCT recipient’s characteristics
If necessary, blood transfusion therapy was carried out according to ABO-status and general recommendations [6]. Statistical analysis was performed using IBM SPSS Statistics version 13.0 by the rules and international recommendations for processing and providing the results of HSCT [19] and include following statistical methods: descriptive statistics for quantitative variables, parametric statistics, description of nominal variables (ABO-incompatibility impact assessment on the development of GvHD); overall survival (OS) analysis was performed by Kaplan-Mayer method using logrank test. To reveal the factors associated with engraft ment terms, a logarithmic utility function (logworth) was used. Th e role of various factors infl uencing posttransplant period and chimerism development was assessed by multivariate analysis (Cox regression). The difference between individual indicators was considered statistically signifi cant at p<0.05.
Results
Impact of ABO blood groups and Rhesus factor on the allo-HSCT effectiveness
In the present study, comprehensive analysis on the impact of ABO- and Rhesus-incompatibility on allo-HSCT effi ciency and risk of complications was performed. Patient's ABO blood group, as an independent parameter, did not aff ect 1-year OS in patients with malignant diseases in allo-HSCT (n=1366), p=0.48. At the same time, negative (n=186) or positive (n=1180) Rhesus factor in the patients proved to be a valuable predictive marker, since its negative status aff ected 1-year OS in allo-HSCT – 48%, with respective average value of 8.1 months, (HR 0.324; 95% CI 7.553 – 8.822), and 59% (average – 8.8 months, HR 0.126; 95% CI 8.605 – 9.101), being signifi cantly diff erent at p=0.01 (Fig. 1).
Rhesus system antigens have a much lower degree of immunogenicity compared to potential eff ects of ABO system, but it can contribute to allo-sensibilisation and promotion of hemolytic complications, thereby reducing the effi ciency of allo-HSCT, which was confi rmed in this study. When comparing pre-transplant RBC phenotypes in the patients with malignancies (n=1175), the following combinations have been found to aff ect the one-year OS (Fig. 2):
- DCCee (n=197) vs ddccee (n=157), 65% (mean, 9.5 months; HR 0.283; 95% CI 8.945-10.056) and 50% (median, 11.4 months; HR 0.348; 95% CI 7.706-9.069), respectively, p=0.006;
- Dccee (n=450) vs ddccee (n=157), 63% (mean – 9 months, HR 0.198; 95% CI 8.672-9.45) and 50%, respectively, p=0.025.
Studying clinical eff ects and outcomes depending on the Rh antigen status of the donor (n=998) confi rm the assumption of a more pronounced negative eff ects of homozygous and D-negative Rh phenotypes upon overall patient survival (Fig. 3):
- DCcEe (n=124) vs DCcee (n=389), 67% and 58%, respectively, (χ2 – 5.454) p=0.019;
- DCcEe (n=124) vs ddccee (n=158), 67% and 53%, respectively, (χ2 – 5.985) p=0.014.
Thus, presence of negative Rhesus factor in the patients (p=0.01) corresponding to the ddccee phenotype (p=0.006), and negative Rhesus factor in graft donor (ddccee phenotype, p=0.014), is associated with a decrease in 1-year OS in patients with malignant diseases, compared with patient’s positive Rhesus and phenotypes DCCee, Dccee and graft donor’s phenotype DCcEe, respectively.
Figure 1. One-year OS in patients with malignant diseases after allo-HSCT depending on the patient’s Rh status
Figure 2. One-year OS in patients with malignant diseases after allo-HSCT, depending on the patient’s erythrocytes Rh phenotype
Figure 3. One-year OS in patients after allo-HSCT, depending on graft donor’s erythrocyte phenotype
The impact of ABO-mismatches on OS and the risk of GvHD development in allo-HSCT
In our study, ABO-incompatibility (n=1428) was documented in 54.6% of allo-HSCT cases (n=780), with major or minor mismatch shown, respectively in 37.8% (n=295), and 45.4% of the cases (n=354); and bidirectional incompatibility having been registered in 16.8% of the cohort (n=131), which is slightly more frequent compared to the worldwide data [4], due to specifi c variability of the gene polymorphisms in the multinational population of Russian Federation, and a significant number of graft s from the foreign unrelated donors used at our HSCT Center.
Th e authors opinion and literature data on the impact of ABO-incompatibility on OS are contradictory since most of them did not prove a negative infl uence upon HSCT outcome. However, the 10-year experience of French BMT group (n=1108) indicate to a negative impact of minor ABO-incompatibility in allo-HSCT patients treated with RIC combination with fl udarabine and low-dose total body irradiation or fl udarabine and busulfan with rabbit ATG, along with absence of remission, and inclusion of ATG>10mg/kg into the GvHD prophylaxys schemes [20].
According to our data, minor ABO-incompatibility in patients with leukemia in remission (n=600) was associated with reduced D+100 OS rates when compared with ABO-compatible allo-HSCT, p=0.05 (Fig. 4): in ABO-compatible patient/donor HSCT, 91% (n=262, a mean of 95 days, HR 0.998; 95% CI 93.32-97.23); for major ABO-incompatibility, 85% (n=117, a mean of 92 days, HR 1.809; 95% CI 89.088-96.179); for minor ABO mismatches, 85% (n=163, an average value of 92 days, HR 1.527; 95% CI 89.324-95.309), and for bidirectional incoompatibility, 93% (n=58, average level of 95 days, HR 1.703; 95% CI 93.207-99.883), respectively. Further analysis was performed according to the type of ABO-incompatibility in combination with conditioning regimens, GvHD prophylaxis, taking into account diff erent degree of myeloablation, mechanisms of immunosuppression and possible risk potentiation for immune complications. A combination of MAC and major ABO-incompatibility in patients with leukemia in remission (n=215) was found to be associated with a decreased OS at 100-days aft er allo- HSCT, if compared with ABO-compatible allo-HSCT, p=0.025 (Fig. 5) which should be taken into account when choosing the conditioning treatment mode. I.e., the OS value for ABO-compatible patients (n=103) was 91% (average of 95 days, HR 1.598; 95% CI 91.885-98.148), in the pairs with major ABO-incompatibility (n=37), the OS value was 76% (average, 88 days, HR 3.765; 95% CI 80.95-95.709). The 100-d OS in cases of minor ABO mismatch (n=56) was 82% (average, 91 days, HR 2.762; 95% CI 86.039-96.868); for bidirectional incompatibility, (n=19), the OS was 89% (average, 93 days, HR 4.364; 95% CI 84.831-101.937).
Figure 4. OS rates for the D+100, depending on the type of ABO-incompatibility in patients with leukemia in remission with allo-HSCT
Figure 5. OS rates on D+100 depending on the type of ABO-incompatibility and MAC in patients with leukemia in remission
Discussion
A high risk for ABO-incompatibility is an additional factor potentiating immunological reactivity, thus increasing risk of GvHD and possible hemolytic complications remains controversial. A number of publications noted higher frequency of acute GvHD grade III-IV in the case of major and minor ABO-incompatibility [21]. On the other hand, a group of scientists from Seattle presented data from the large US National Bone Marrow Donor Program showing no signifi cant diff erence in the development of acute GvHD depending on the ABO-incompatibility type [22].
Results of our study indicate that the type of ABO-incompatibility: major (n=123), minor (n=167) or bidirectional (n=61) did not increase either severity, or incidence of acute GvHD (grade I-IV) in patients with leukemia transplanted in remission (n=626), compared to ABO-compatible HSCT (n=275), p=0.85. Acute GvHD developed in ABO-compatible HSCT in 52% of cases (n=143), in major ABO-incompatibility, 48.8% (n=60), in minor ABO-mismatch, 50.9% (n=85), in bidirectional mismatch, 55.7% (n=34), respectively.
Likewise, the type of ABO-incompatibility: major (n=123), minor (n=167), bidirectional (n=61); did not increase the risk of chronic GvHD in patients with leukemia treated in remission (n=626) compared to ABO-compatible HSCT (n=275), p=0.21. Chronic GvHD developed in ABO-compatible HSCT in 26.5% of cases (n=73); in major ABO-incompatibility, 24.4% of cases (n=30); in minor, 24% of cases (n=40); in bidirectional, 37.7% (n=23), respectively.
The impact of ABO-incompatibility on engraftment
According to the results of our study, in general cohort of patients with allo-HSCT, the leukocyte recovery >1.0x109/l was observed on day 18 (mean ± standard deviation – 20±10.4); neutrophil recovery >0.5x109/l – on day 17 (20.5±13.6); platelet recovery >20x109/l – on day 14 (21±17.8); platelet recovery >50x109/l – on day 16 (23.2±15). Th e most significant factors which determined time of engraft ment were as follows: HLA–match (logworth, 15.1), graft source (logworth, 7.05), type of allo-HSCT (logworth 6.4), conditioning regimen (logworth, 4.05). Th e factors which increased the engraft ment time were as follows: 9/10 HLA-match, MAC regimen, bone marrow as a source of transplant. In turn, ABO- and Rhesus-incompatibility had a much smaller impact on neutrophils and platelets engraft ment timeline: ABO-incompatibility (logworth of 0.87), blood group of the donor (logworth, 0.34), patient’s erythrocyte phenotype (logworth, 0.33), donor’s Rhesus factor (logworth, 0.27), donor’s erythrocyte phenotype (logworth, 0.001).
However, as exemplifi ed by 240 recipients of allo-HSCT, the diff erences in recovery time of erythrocyte counts on D+50 proved to be dependent on ABO-incompatibility, i.e., the patients from ABO-compatible donor/patient pairs achieved RBC recovery in 23.8% of cases, and those with ABO-incompatibility, in 10% (p=0.01).
Th e results of this study suggest that the 100% donor chimerism for ABO blood groups was reached in 159 of 240 patients (17 to 229 days, a median of 84 days). In 81 patients, the results could not be assessed due to their death in early posttransplant period (n=50); inability to identify diff erences, due to identity for ABO-, Rhesus-system (D, C, c, E, e) and Kell markers (n=7); lack of laboratory data due to incomplete patient's data obtained posttransplant (n=24). Primary diagnosis (p=0.87), disease status (p=0.69), allo- HSCT type (p=0.26), graft source (p=0.28), degree of HLA match (p=0.62) and conditioning regimens (p=0.39) did not have a negative impact on blood group conversion terms. ABO-incompatibility was the only identifi ed factor increasing chimerism time development (p=0.0001).
For ABO-compatible allo-HSCT with Rh incompatibility (n=52), the time to achieve 100% chimerism was 95±44 days (31-226 days, HR 6,106; 95% CI 82.9-107.4), with major ABO-incompatibility (n=29) – 109±51 days (27-229 days, HR 9.642; 95% CI 89.9-129.4), with minor (n=57) – 67±22 days (17-109 days, HR 3,032; 95% CI 61-73,1), with bidirectional mismatches (n=21) – 72±16 days (48-117 days, HR
3,515; 95% CI 65,3-80).
Negative effect of ABO-incompatibility type on erythroid time recovery, is refl ected in posttransplant transfusion therapy intensiveness (p=0,003). Th e average number of transfusions of blood components was 25 units in major ABO-incompatibility (p=0.001); 16.5, in minor mismatch (p=0.006); 13.6, in bidirectional (p=0.005); 15.1, in ABO-compatible allo-HSCT (p=0.001), respectively.
HSCT complications associated with ABO-incompatibility
Additional attention is paid to the development of specifi c complications associated with ABO-incompatibility. Clinical manifestations in this case may be due to localization of ABO system antigens, which are represented not only on erythrocytes, but also on other cells and tissues: platelets, lymphocytes, endothelium of blood vessels and organs (kidneys, liver, heart) circulating in plasma [23].
According to our data, the risk of immune complications in allo-HCT (n=1158) is 2.8% (n=33) versus 4.1% in the presence of ABO-incompatibility (n=638, p=0.02), as seen from Table 3. A low number of cases and mortality (n=3) may indicate adequate prevention, timely and eff ective treatment.
Design of OS predictive models in allo-HSCT
One of the main objectives in multivariate analysis was to identify factors and their combinations that aff ect OS in allo-HSCT, and to create a mathematical model for predicting the probability of potential complications, which will allow for timely prophylaxis and treatment. The study was based on Cox regression with preliminary exploratory analysis for patients with malignant diseases, which was performed as a Kaplan-Meier test for nominal variables-factors aff ecting the outcome of treatment [24]. As a result of the analysis, the following predictors aff ecting OS were identified: degree of HLA-match, presence of acute GvHD, major ABO-incompatibility, allo-HSCT type, status of the underlying disease, and use of ATG for GvHD prophylaxis (Fig. 6).
Our valid predictive model of 100-day OS may serve such an example, which included patients with leukaemia (n=140) from 9/10 HLA-matched related and unrelated donor, in case of engraft ment up to D+31 (Fig. 7).
Figure 6. OS predictors in allo-HSCT patients with malignant diseases
Figure 7. 100-day OS predictive model in patients with allo-HSCT with 9/10 HLA-match with engraftment up to D+31
Note: Profile 1: MAC, major ABO-incompatibility, GvHD prophylaxis – cyclophosphamide containing schemes; Profi le 2: MAC, major ABO-incompatibility, GvHD prophylaxis «cyclosporine A + methotrexate» or « tacrolimus + methotrexate». Table 3. Development of immune complications in allo-HSCT depending on the ABO-incompatibility type
Table 3. Development of immune complications in allo-HSCT depending on the ABO-incompatibility type
Conclusion
The data presented in this study suggest that ABO-incompatibility may be a negative factor reducing eff ectiveness of treatment in allo-HSCT, especially in the early posttransplantation period and during the fi rst year posttransplant. Adverse eff ects of ABO-incompatibility are realized through allosensitization, increasing the frequency of hemolytic complications and delaying erythroid recovery.
It seems that the main tool for minimizing the ABO-incompatibility consequences is the donor graft preparation based on ABO-incompatibility type, which allows achieving low frequency and severity of possible hemolytic complications.
The next factor of important value is the replacement transfusion therapy, which should be based on red blood cells chimerism level and comply with the principles to use the most leukocyte depleted blood components, which can improve the efficiency of blood transfusions and reduce the risk of posttransfusion reactions and complications.
Thus, when choosing an allogeneic bone marrow donor, giving priority to a higher degree of HLA-match and CMV-status in "recipient-donor" pair, it is also optimal to choose, if possible, an ABO- and Rhesus compatible donor.
Conflict of interests
The authors have noconflict of interest to declare.
References
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2. Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: state of art, issues and prospects. Russian Journal of Pediatric Hematology and Oncology. 2015; 2(2); 28-42 (In Russian).
3. Rowley SD, Donato ML, Bhattacharyya P. Red blood cell-incompatible allogeneic hematopoietic progenitor cell transplantation. Bone Marrow Transplantation. 2011; 46; 1167-1185.
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6. Booth GS, Gehrie EA, Bolan CD, Savani BN. Clinical guide to ABO-incompatible allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013; 13: 1152-1158.
7. Worel N, Greinix HT, Schneider B, Kurz M, Rabitsch W, Knöbl P, Reiter E, Derfl er K, Fischer G, Hinterberger W, Höcker P, Kalhs P. Regeneration of erythropoiesis aft er related- and unrelated-donor BMT or peripheral blood HPC transplantation: a major ABO mismatch means problems. Transfusion. 2000;40: 543-550.
8. Seebach JD, Stussi G, Passweg JR, Loberiza FR Jr, Gajewski JL, Keating A, Goerner M, Rowlings PA, Tiberghien P, Elfenbein GJ, Gale RP, van Rood JJ, Reddy V, Gluckman E, Bolwell BJ, Klumpp TR, Horowitz MM, Ringdén O, Barrett AJ. ABO blood group barrier in allogeneic bone marrow transplantation revisited. Biol Blood Marrow Transplant. 2005;11:1006-1013.
9. Remberger M, Watz E, Ringden O, Mattsson J, Shanwell A, Wikman A. Major ABO blood group mismatch increases the risk for graft failure aft er unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007; 13:675-682.
10. Ahmed I, Teruya J, Murray-Krezan C, Krance R. Th e incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post fi rst and second hematopoietic stem cell transplant. Pediatr Transplant. 2015;19(4):391-398.
11. Jagasia M, Arora M, Flowers MED, Chao NJ, McCarthy PL, Cutler CS, Urbano-Ispizua A, Pavletic SZ, Haagenson MD, Zhang MJ, Antin JH, Bolwell BJ, Bredeson C, Cahn JY, Cairo M, Gale RP, Gupta V, Lee SJ, Litzow M, Weisdorf DJ, Horowitz MM, Hahn T. Risk factors for acute GVHD and survival aft er hematopoietic cell transplantation. Blood 2012;119:296-307.
12. Atay D, Erbey F, Akcay A, Ozturk G. Is ABO mismatch another risk factor for allogeneic hematopoietic stem cell transplantation in pediatric thalassemic patients? Pediatr Transplant 2015; 19(6); 645-651.
13. Gutiérrez-Aguirre CH, Gómez-De-León A, Alatorre-Ricardo J, Cantú‐Rodríguez OG, González‐Llano O, Jaime‐Pérez JC, Mancías‐Guerra C, Flores‐Jiménez JA, Gómez‐Almaguer D. Allogeneic peripheral blood stem cell transplantation using reduced-intensity conditioning in an outpatient setting in ABO-incompatible patients: are survival and graft -versus-host disease diff erent? Transfusion. 2014;54(5):1269-1277.
14. Przepiorka D, Weisdorf D, Martin P. 1994 Consensus Conference on acute GVHD grading. Bone Marrow Transplant. 1995;15:825.
15. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. National Institutes of Health Consensus development project on criteria for clinical trials in chronic graft -versus-host disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2005;11:945-955.
16. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, Kerr H, Stratton P, Duarte RF, McDonald GB, Inamoto Y, Vigorito A, Arai S, Datiles MB, Jacobsohn D, Heller T, Kitko CL, Mitchell SA, Martin PJ, Shulman H, Wu RS, Cutler CS, Vogelsang GB, Lee SJ, Pavletic SZ, Flowers ME. National Institutes of Health Consensus development project on criteria for clinical trials in chronic graft -versus-host disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2015; 21(3): 389-401.
17. The National Hematology Society. Clinical guidelines for the diagnosis and treatment of acute myeloid leukemia in adults. II Congress of Hematologists of Russia 2014 (In Russian).
18. Ortho BioVue System Handbook 2015: 1-37.
19. Szydlo RM. Statistical Evaluation of SCT data, haematopoietic stem cell transplantation. Th e EBMT Handbook, 6th Edition (Eds: Apperley, Carreras, Gluckman, Masszi) // Publ: European School of Haematology 2012: 612-628.
20. Michallet M, Le QH, Mohty M, Prébet T, Nicolini F, Boiron JM, Esperou H, Attal M, Milpied N, Lioure B, Bordigoni P, Yakoub-Agha I,Bourhis JH, Rio B,Deconinck E, Renaud M, Chir Z, Blaise D. Predictive factors for outcomes aft er reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Société Française de Greffe de Moelle et de Th érapie Cellulaire. Exp Hematol 2008; 36:535-544.
21. Kimura F, Sato K, Kobayashi S, Ikeda T, Sao H, Okamoto S, Miyamura K, Mori S, Akiyama H, Hirokawa M, Ohto H, Ashida H, Motoyoshi K. Impact of ABO-blood group incompatibility on the outcome of recipients of bone marrow transplants from unrelated donors in the Japan Marrow Donor Program. Haematologica 2008; 93:1686-1693.
22. Goldman J, Liesveld J, Nichols D, Heal J, Blumberg N. ABO incompatibility between donor and recipient and clinical outcomes in allogeneic stem cell transplantation. Leuk Res. 2003;27: 489-491.
23. Gehrie EA, Cates JM, Nian H, Olson SJ, Young PP. Blood group A antigen expression on cardiac endothelium is highly individualized: Possible implications for transplantation. Cardiovasc Pathol 2013; 22:251-256.
24. Kleinbaum DG, Klein M. Survival Analysis. A Self-Learning Text. Second Edition, Springer Science & Business Media, Inc 2005.
2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20878" ["VALUE"]=> array(2) { ["TEXT"]=> string(4105) "<p style="text-align: justify;"> В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ). </p> <h2 style="text-align: justify;">Результаты</h2> <p style="text-align: justify;"> АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85. </p> <h2 style="text-align: justify;">Заключение</h2> <p style="text-align: justify;"> АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что<br> требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3901) "
В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.
Пациенты и методы
В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).
Результаты
АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.
Заключение
АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что
требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.
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Kucher <sup>1</sup>, Dmitrii E. Pevtcov <sup>1</sup>, Polina S. Kuga <sup>1</sup>, Boris I. Smirnov <sup>1</sup>,<sup>2</sup>, Alexander L. Alyanskiy <sup>1</sup>, Natalia E. Ivanova 1, Maria A. Estrina <sup>1</sup>, Elena V. Babenko <sup>1</sup>, Burkhonidin B. Bakhovadinov <sup>1</sup>, Ludmila S. Zubarovskaya <sup>1</sup>, Boris V. Afanasyev <sup>1</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(372) "Maxim A. Kucher 1, Dmitrii E. Pevtcov 1, Polina S. Kuga 1, Boris I. Smirnov 1,2, Alexander L. Alyanskiy 1, Natalia E. Ivanova 1, Maria A. Estrina 1, Elena V. Babenko 1, Burkhonidin B. Bakhovadinov 1, Ludmila S. Zubarovskaya 1, Boris V. Afanasyev 1" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20881" ["VALUE"]=> array(2) { ["TEXT"]=> string(384) "<sup>1</sup> R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St.P etersburg, Russia<br> <sup>2</sup> St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(348) "1 R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St.P etersburg, Russia
2 St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20882" ["VALUE"]=> array(2) { ["TEXT"]=> string(2841) "<p style="text-align: justify;"> Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients. </p> <h2 style="text-align: justify;">Patients and methods</h2> <p style="text-align: justify;"> From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created. </p> <h2 style="text-align: justify;">Results</h2> <p style="text-align: justify;"> ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of<br> ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, ABО-incompatibility, complications. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2637) "
Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.
Patients and methods
From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.
Results
ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.
Conclusion
ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.
Keywords
Hematopoietic stem cell transplantation, ABО-incompatibility, complications.
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Kucher <sup>1</sup>, Dmitrii E. Pevtcov <sup>1</sup>, Polina S. Kuga <sup>1</sup>, Boris I. Smirnov <sup>1</sup>,<sup>2</sup>, Alexander L. Alyanskiy <sup>1</sup>, Natalia E. Ivanova 1, Maria A. Estrina <sup>1</sup>, Elena V. Babenko <sup>1</sup>, Burkhonidin B. Bakhovadinov <sup>1</sup>, Ludmila S. Zubarovskaya <sup>1</sup>, Boris V. Afanasyev <sup>1</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(372) "Maxim A. Kucher 1, Dmitrii E. Pevtcov 1, Polina S. Kuga 1, Boris I. Smirnov 1,2, Alexander L. Alyanskiy 1, Natalia E. Ivanova 1, Maria A. Estrina 1, Elena V. Babenko 1, Burkhonidin B. Bakhovadinov 1, Ludmila S. Zubarovskaya 1, Boris V. Afanasyev 1" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(372) "Maxim A. Kucher 1, Dmitrii E. Pevtcov 1, Polina S. Kuga 1, Boris I. Smirnov 1,2, Alexander L. Alyanskiy 1, Natalia E. Ivanova 1, Maria A. Estrina 1, Elena V. Babenko 1, Burkhonidin B. Bakhovadinov 1, Ludmila S. Zubarovskaya 1, Boris V. Afanasyev 1
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20882" ["VALUE"]=> array(2) { ["TEXT"]=> string(2841) "<p style="text-align: justify;"> Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients. </p> <h2 style="text-align: justify;">Patients and methods</h2> <p style="text-align: justify;"> From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created. </p> <h2 style="text-align: justify;">Results</h2> <p style="text-align: justify;"> ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of<br> ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, ABО-incompatibility, complications. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2637) "
Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.
Patients and methods
From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.
Results
ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.
Conclusion
ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.
Keywords
Hematopoietic stem cell transplantation, ABО-incompatibility, complications.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2637) "Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.
Patients and methods
From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.
Results
ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.
Conclusion
ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.
Keywords
Hematopoietic stem cell transplantation, ABО-incompatibility, complications.
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" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(348) "1 R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St.P etersburg, Russia
2 St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
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Афанасьев 1" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(538) "Mаксим A. Кучер 1, Дмитрий Э. Певцов 1, Полина С. Куга 1, Борис И. Смирнов 1, 2, Александр Л. Алянский 1, Наталья Е. Иванова 1, Мария А. Эстрина 1, Елена В. Бабенко 1, Бурхонидин Б. Баховадинов 1, Людмила С. Зубаровская 1, Борис В. Афанасьев 1" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20878" ["VALUE"]=> array(2) { ["TEXT"]=> string(4105) "<p style="text-align: justify;"> В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ). </p> <h2 style="text-align: justify;">Результаты</h2> <p style="text-align: justify;"> АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85. </p> <h2 style="text-align: justify;">Заключение</h2> <p style="text-align: justify;"> АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что<br> требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3901) "
В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.
Пациенты и методы
В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).
Результаты
АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.
Заключение
АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что
требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3901) "В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.
Пациенты и методы
В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).
Результаты
АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.
Заключение
АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что
требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.
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2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия
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Introduction
Allo-HSCT is a well-defined treatment mode for high-risk acute lymphoblastic leukemia (ALL) [1]. However, relapse still remains the major cause of treatment failure in children with ALL, even among patients who received transplantation during hematologic remission [2-4]. High risk of relapses aft er allo-HSCT arises, mostly, due to selection of the patients with signs of poor clinical prognosis (refractory to chemotherapy, unfavorable cytogenetic or molecular genetic alterations) [5, 6], whereas the patients with more favorable prognosis undergo standard chemotherapy treatment [1, 7]. Th e relapses occur in 30-35% of patients with ALL and it is one of the most common causes of mortality aft er allo-HSCT [2, 3, 8]. Survival of patients who experienced relapse is about 3-19% depending on the time between allo-HSCT and relapse [9]. In the case of clinical posttransplant relapse further treatment options are limited and often ineffective [10, 11]. For example, a second allo-HSCT can give a chance to cure such patients, but it is associated with high orbidity and mortality. Donor lymphocyte infusion (DLI) has a limited success if it is started during hematological relapse [12]. At the same time, immunotherapy at the stage of early relapse (before hematological manifestation), when the leukemia clone is still small, is more eff ective than relapse treatment [12-15]. Therefore, the study of early signs of disease recurrence is particularly important.
The early signs of impending ALL relapse aft er allo-HSCT are usually detected by MRD monitoring using the following means: 1) fl ow cytometry of leukemia-associated immunophenotype, or quantitative real-time PCR of chimeric oncogenes, or clonal rearrangements of immunoglobulin molecules, or T-cell receptor genes (Ig/TCR-PCR) [16-18]; 2) donor chimerism monitoring [19, 20].
A clone of ALL cells originating from a single primary-transformed cell carries identical Ig/TCR rearrangements in all the malignant cells. Th erefore, the rearrangements detected in ALL samples at diagnosis could serve as specifi c molecular markers for MRD monitoring. Ig/TCR rearrangements allow MRD monitoring in the vast majority of ALL patients, and comparing the results aft er allo-HSCT [21].
MRD monitoring in pediatric ALL by Ig/TCR rearrangements has widely been accepted as a reliable prognostic factor of relapse during chemotherapy and before allo-HSCT [1]. However, its application aft er allo-HSCT has been less clearly defi ned and still controversial. Th e signifi cance of precise quantifi cation of MRD aft er transplantation is not completely established. Th e aim of the study was to evaluate the impact of quantitative MRD on outcomes of allo-HSCT.
Patients and methods
Our study included 45 patients with ALL or biphenotypic AL who underwent the fi rst allo-HSCT at the Center for Pediatric Oncology, Hematology and Immunology from 2010 to 2017. Initial screening for Ig/TCR clonal rearrangements was performed in all the patients. MRD monitoring using Ig/TCR targets was performed in 35 of them (eight patients had no target markers, 1 had no primary engraft ment, no sample material was obtained aft er 1 alloHSCT). Basic characteristics of 35 patients with ALL/biphenotypic AL enrolled in the posttransplant MRD studies are listed in Table 1. The recipient age at the time of transplantation was 2-25 (median 11) years. All parents or guardians signed the informed consent. All the patients received myeloablative conditioning (MAC), except of one with Nijmegen syndrome/ALL who underwent a reduced-intensity conditioning regimen (RIC).
For MRD assays, bone marrow (BM) and peripheral blood (PB) samples were collected on days +30, +60, +100, +180, +365 aft er alloHSCT, and every six months thereaft er. Mononuclear BM cells were isolated in the Histopaque density gradient (Sigma-Aldrich, USA). DNA extraction was carried out by phenol-chloroform method. DNA quality and concentration was evaluated with a NanoDrop 2000c spectrophotometer (Th ermoFisher Scientifi c, USA).
Genomic DNA samples at diagnosis were screened by PCR for clonal IgH, IgK immunoglobulin and rearrangements of TCRD, TCRG, TCRB genes. DNA amplifi cation was performed with primers, recommended by BIOMED-1 Concerted Action [22] for IgK and TCRG genes, and a report by Chim et al. for IgH gene [23]. The TCRD gene was amplified according to Taube et al. [24], and TCRB by BIOMED-2 Concerted Action [21]. Further on, the specifi c PCR products were evaluated by heteroduplex analysis by polyacrylamide gel technique, then being cut from the gels, purifi ed and sequenced in the ABI PRISM 3130 Genetic Analyzer (Applied Biosystems, USA) in both directions. Detailed description of the detection procedure of diff erent Ig/TCR rearrangements in ALL was reported in our previous publications [25, 26]. Allele-specifi c oligonucleotides (ASO) primers were selected to cover the N region of rearrangement, specifi cally, for the 3’ end of primer. Secondary structures were avoided. At least two different ASO-primers were designed for each rearrangement point and tested, in order to choose the best system for MRD quantification.
Table 1. Characteristics of patients with ALL and biphenotypic AL (n= 35) included in the MRD study after allo-HSCT
ASO-primers and germline TaqMan probe approach were applied for RQ-PCR analysis in CFX96 machine (Bio-Rad, USA). PCR amplifi cation was performed in 20μL reaction mix with TaqMan Universal PCR Master Mix (Applied Biosystems, USA), 500 ng of genomic DNA, 500 ng of each primer and 150 ng of fl uorescent TaqMan probe labeled with 3’FAM, 5’BHQ. Th e panel of germline primers and probes was published elsewhere [27]. For MRD quantifi cation, we prepared serial ten-fold dilutions of diagnostic DNA in polyclonal controls to make a standard curve construction. To normalize the individual results, the same samples were amplifi ed with primers for albumin reference gene [28]. A standard curve for the albumin gene was plotted with diagnostic DNA serially diluted in water. Standard Quantity (SQ, mean of triplicate) was automatically generated by CFX96 based on standard curve for both albumin and target. Interpretation of MRD analysis results was performed in accordance with the guidelines published by the European Study Group on MRD detection [29].
RNA was isolated from the BM mononuclear cells with TRIzol reagent (Th ermo Fisher Scientifi c, USA). MRD monitoring based on measuring expression of chimeric oncogenes TEL-AML1, BCR-ABL1, MLL1-AF4 was performed by quantitative real-time PCR of the cDNA. Th e real-time PCR was performed in 25-μl volume containing 2x TaqMan Universal PCR Master Mix (Applied Biosystems, USA), 300 nM primers, 200 nM TaqMan probes and 5 μl of cDNA or standards. Commercial standards (Qiagen, Germany) were used for calibration of absolute gene copy numbers. The PCR conditions were as follows: 2 min, 50°C; 10 min, 95°C; 50 cycles (95°C, 15 sec; 60°C, 60 sec).
MRD detection was also performed by multiparametric fl ow cytometry (FC) of mononuclear cell suspensions (1 million cells/mL, 100 μl). A panel of monoclonal antibodies conjugated with fl uorescent labels FITC, PE, PC5, PC7 (Beckman Coulter, USA). In addition, we used reagents for fi xation and permeabilization (Becton Dickinson, USA) for detection of intracellular antigens. Following incubation and staining, the cells were washed once in phosphate buff er saline with subsequent fi xation in 1% paraformaldehyde. FC-analysis was carried out with the Navios fl ow cytofl uorimeter (Beckman Coulter, USA) using the CXP program.
Donor chimerism was determined by real-time PCR of InDel markers and multiplex PCR of short tandem repeats (STR) in BM and/or PB on +30, +45, +60, + 80, +100, +140, +180, +245, + 365 days aft er allo-HSCT and, thereaft er, every six months. In case of mixed chimerism (MC), the studies were conducted more oft en. AmpFlSTR® SGM Plus® PCR Amplification Kit (ABI, UK) was used for amplifi cation of STR markers, PCR products were separated by capillary electrophoresis using 3130 Genetic Analyzer (Applied Biosystems, USA). Distinct alleles were identifi ed by means of GeneMapper soft ware (Applied Biosystems, USA). InDel-PCR was performed as previously described [30-32]. Full donor chimerism (FDC) was defi ned as >99% donor cells, and mixed chimerism was accepted at 5-99% donor cells.
Statistical evaluation was performed by non-parametric methods using the STATISTICA approach. Overall survival was defi ned as the time period between allo-HSCT and death, or to the last observation date. Treatment-related mortality (TRM) was defi ned as a death in complete remission state (CR) without preceding relapse, from any causes associated with HSCT procedure. Event-free survival (EFS) was determined as survival without TRM, relapse, rejection, or secondary tumor. Th e time to clinical events (relapse, TRM, GVHD) was measured from the date of alloHSCT. Kaplan-Meier estimates were performed to predict probabilities for overall survival and EFS [33]. Th e log-rank test was used for comparisons. Cumulative incidence (CI) curves were calculated to assess incidence of relapse (CIR) and TRM [34]. Gray’s test was used for comparisons of CIs [35]. Fisher’s exact test was applied in order to compare the patients’ categorical data. Th e results of statistical evaluation were considered signifi cant at p<0.05.
Results
Survival of patients with different MRD status after allo-HSCT
Ig/TCR clonal rearrangements were identifi ed for 37 of 45 patients (82.2%). Chimeric oncogenes were determined only in 10 (22%) of 45 patients: 5 (11.1%) with MLL-AF4; 4 BCR-ABL1-positive cases (8.9%); one patient (2.2%) with TEL-AML1. MRD monitoring by Ig/TCR rearrangements was performed aft er 35 allo-HSCT that were included into the analysis. Th e median follow-up of the patients surviving aft er allo-HSCT was 3.6 years.
MRD status according to Ig/TCR target was negative in 21 (60%) patients, and only two of them (9.5%) relapsed. Positive MRD was detected in 14 (40%) patients, 7 (50%) of them had isolated bone marrow relapse. Th e three-year CI of relapse was higher in the patients with positive MRD at
any time aft er allo-HSCT (58.3±16.2%) as compared to the patients with negative MRD (10.7±7.4%), p=0.0042 (Fig. 1). Overall survival and EFS were signifi cantly lower in cases of positive MRD (33.2± 14.4% vs 83.6± 8.8%, p=0.008, and 18.9± 11.7% vs 66.6± 11.4%, p=0.002).
In all six patients who reached high MRD levels (>10-3), we observed recurrence of the disease. Only one (16.7%) patient relapsed of six children with intermediate MRD levels (10-4-10-3). Two patients with MDR level <10-4 retained their CR state. Generally, in cases of positive MRD, the patients with relapse showed higher levels of preceding MRD (1.6*10-1-2.7*10-4), than the relapse-free patients (<10-5-10-3), as seen from Table 2. The three-year cumulative incidence (CI) of relapse for the patients with non-detectable MRD, with MRD ≤10-3, and >10-3 was, respectively, 10.7±7.4% vs 14.6±14.6% vs 100% (p<0.0001). Overall survival rates (OS) were 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), and EFS rates were 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012), respectively (Fig. 2).
In two patients, positive MRD was not found in BM cells before relapse. One patient had extramedullary relapse (EMR) in the central nervous system (CNS). In the second patient, a loss of Ig/TCR target was observed in hematological BM relapse.
MRD monitoring with Ig/TCR rearrangements in BM, along with PB, was performed in 10 patients. In seven cases (70%), positive MRD was detected before relapse in both BM and PB. In three patients, MRD was detected in BM only, one of them relapsed. In this patient, MRD was still not detected in PB at the time of relapse.
Figure 1. Probability (CI) of relapse (A), OS (B) and EFS values (C) in the patients with ALL/biphenotypic AL according to MRD status after allo-HSCT
Figure 2. Probability (CI) of relapse (A), OS (B), and EFS (C) in patients with ALL/biphenotypic AL according to MRD levels after alloHSCT. Curves are designated black (MRD –); green (MRD >10-3); or red (MRD <10-3)
Comparison of MRD results obtained by different targets/methods
In nine patients, MRD was monitored by Ig/TCR rearrangements, as well as expression of BCR-ABL1 (n=4), MLL-AF4 (n=4), TEL-AML1 (n=1). In only one case, the results were discordant, i.e., the abovementioned patient who was negative by Ig/TCR target (loss of the target), but he was positive for MLL-AF4. In four patients, MRD was not detected, either by expression of BCR-ABL1 (n=2), MLL-AF4 (n=2), or Ig/TCR targets. Positive MRD was detected by both methods in four patients. Paired points for comparison were available in two patients. In one case, positive MRD was detectable by both approaches (MLL-AF4 and Ig/TCR markers). In another case (patient №12), we observed earlier appearance of MRD in BM as detected by TEL-AML expression (on day +98), than by Ig/TCR marker (detected at the next point of D+124). Hence, the fi rst method seems to be more sensitive (Fig. 3).
Table 2. Time dynamics of MDR in patients with ALL
Figure 3. MRD time course in Patient #12, according to TEL-AML expression and Ig/TCR rearrangement (Igk). Abscissa, gene copy number (log10); ordinate, terms posttransplant
MRD measured by immunophenotyping and Ig/TCR rearrangements was monitored in four patients in parallel (at the same time points aft er HSCT). Negative MRD was detected by both methods in one patient. In three patients, we received discordant results: there were positive MRD values of <10-3 detected by Ig/TCR gene rearrangements, however, being negative by immunophenotyping technique. Nevertheless, negative results were observed in some cases by both methods.
Comparison of MRD data obtained by Ig/TCR and chimerism markers
Donor chimerism monitoring was performed in all 35 patients.
1) Full donor chimerism (FDC) and negative MRD state were detected in 19 patients, only 2 of them have relapsed (Table 3). In one patient with loss of Ig/TCR target, a relapse was diagnosed more than 2 months aft er last chimerism monitoring in BM cells (D+377, late isolated BM relapse). Th e second patient with extramedullary CNS relapse had negative MRD and FDC in PB and BM cells, even at the time of relapse.
2) Mixed chimerism (MC) and negative MRD were detectable in 2 cases. One patient had negative MRD and MC (98.9%) in BM on D +30. Th is patient reached FDC (since +60 day), but died with infectious complications on D +542. Th e second patient showed FDC conversion to increasing MC accompanied by infection, and died on D +78.
3) FDC and positive MRD (up to 1.6*10-1) was observed in 7 patients, two of them have relapsed. Th e patient №12 had BM relapse on D +522, with last testing point at D +347, when full donor chimerism and MRD of 5*10-5 were determined. In the second patient (№13), a BM relapse was diagnosed by the D+226. Slightly decreased chimerism level of 99.1% was registered in blood leukocytes, along with increased MRD level to 15% at the last term before the relapse (D+197). In three patients with FDC, we observed MRD clearance, the rest of them retained their MRD positivity at the last examination.
Table 3. Comparison of MRD and chimerism monitoring data in ALL patients
4) MC and positive MRD was traced in seven patients, five of them had the disease recurrence. Before relapse, an increase of MC and MRD up to 2.2*10-2 was observed in four patients (the fi ft h patient had an early relapse, and only one monitoring point before relapse). Patient №5 with increasing MC has shown graft rejection on D +74 with subsequent autorecovery without ALL reoccurrence, with MRD levels in BM of <10-4 on days +27 to +39, then becoming negative at later terms. Patient №1 had an MC state (98.5% on D+30 in BM and PC) with FDC state achieved by the D +60; this patient is now alive, being in complete remission.
Thus, we have revealed suffi cient concordance between MRD and donor chimerism in 26 (74.3%) out of 35 cases. Th =e most favorable group comprised a subgroup with negative MRD and FDC, an intermediate group consisted of patients with positive MRD and FDC, and the most unfavorable group included the patients with positive MRD and increasing MC. Th e respective 3-year CI of relapse for these groups were as follows: 11.9 ± 8.2% vs 41.7 ± 29.5% vs 80.0 ± 23.9% (p<0.0008); the OS values were 94.4 ± 5.4% vs 44.4 ± 22.2% vs 20.0 ± 17.9% (p=0.0029); EFS probability was 75.0 ± 11.0% vs 25.0 ± 20.4% vs 0% (p<0.0001), respectively (Fig. 4).
Dependence of survival upon MRD and GVHD association
Grade I-IV acute GvHD (aGvHD) was observed in 17 (48.6%) of 35 patients, and six of them were diagnosed with severe aGvHD (grade III-IV). MRD-negative state was registered more oft en in the patients with aGvHD (in 13 of 17 cases), as compared to the GvHD-free cases (8 of 18 patients, p=0.085).
1) Among 13 patients with negative MRD and aGvHD, only 1 (7.7%) patient had relapse in CNS.
2) Among eight patients with negative MRD without aGvHD, nobody has relapsed.
3) None of the four patients with positive MRD and aGvHD relapsed. MRD clearance occurred in 4 patients (40%) on the days +100–+150.
4) In seven (70%) of 10 patients with positive MRD without aGvHD disease reoccurred. Four of these 10 patients received DLI, 2 of them experienced relapse despite GvHD signs observed aft er IDL.
Clinical outcomes of the patients with negative MRD without aGvHD, patients with negative MRD with aGvHD, and patients with positive MRD and aGvHD were nearly similar, being defi nitely better than in the group of aGvHD-free patients with positive MRD. Th e three-year CI of relapse rates were as follows: 20.0±20.0% vs 7.7±7.7% vs 0% vs 80.0±20.2% (p=0.008).Th e respective, overall survival probability was 80.0±17.9% vs 84.6±10.0% vs 66.7±27.2% vs 18.0±15.1% (p=0.026). Th e EFS values for these subgroups were: 60.1±21.9% vs 67.3±13.6% vs 66.7±27.2% vs 0% (p=0.0004), respectively (Fig. 5).
Figure 4. Probability of relapse (A), OS (B) and EFS (C) in patients with ALL/biphenotypic AL according to MRD and chimerism after allo-HSCT. Curves are designated black (MRD+/FDC); green (MRD+/FDC); or red (MRD-/ mixed chimerism increase)
Discussion
The MRD monitoring can help to identify presence of tumor cells that survived aft er the conditioning. However, this assay is applicable only for patients with a defi ned marker (chimeric oncogenes, mutations, Ig/TCR rearrangements or leukemia-associated immunophenotype). Identifi cation of tumor-specifi c mutations is the most accurate diagnostic approach showing high specifi city. However, the structure of these mutations should be suitable for MRD monitoring, with a sensitivity of, at least, 10-4 [36]. In ALL monitoring, quantitative real-time PCR (qPCR) allows to determine MRD by specifi c chimeric oncogenes/transcripts, point mutations and other rearrangements, such as BCR-ABL1, PML/ RARa, RUNX1-RUNX1T1 (AML1-ETO), CBFB-MYH11, MLL translocations, at a high sensitivity of 10-5-10-6 [37]. Chimeric oncogenes are detected only in a small number of patients with ALL [36, 38]. In our study, they were found only in 11% of transplantation patients. Th ere exists another alternative to chimeric oncogenes and mutations in ALL, i.e., clonal rearrangements of Ig and TCR genes, which are an attractive marker for MRD monitoring, being detectable in vast majority of ALL patients (up to 90-95% [36, 37], 82% of our patients).
Analytical sensitivity is an important aspect of MRD assay, since an arising leukemic clone posttransplant is regarded as an unfavorable event. MRD monitoring with Ig/TCR has a good sensitivity up to 10-4-10-5. Measurement of chimeric oncogene expression may be an even more sensitive approach in some cases, since a single malignant cell may contain several dozens or even thousands copies of chimeric oncogenes. It increases sensitivity up to 1 lg10, thus allowing earlier detection of tumor cells aft er allo-HSCT than with DNA-targets. However, the predictive value of individual methods and expression markers is not well defi ned. By contrast, MRD monitoring procedure with Ig/TCR rearrangements has been standardized and provides comparable results obtained from diff erent patients, which makes it possible to assess not only the presence of MDR aft er alloHSCT, but also takes its levels into account [4, 36, 37, 39]. Immunophenotyping using fl ow cytometry has a lower sensitivity (up to 10-4) than PCR-based methods. Its application for MRD monitoring aft er allo-HSCT is limited due to diffi culties with interpretation of results [40]. Bone marrow regeneration after allo-HSCT makes it diffi cult to identify leukemic cells on the background of normal lymphoid precursors [1].
It is also necessary to consider the stability of various MRD markers [36]. In rare cases, the Ig/TCR target can be lost due to somatic mutations accumulating in tumor cells [41, 42], what we have found in one case (2.9% of total group). RQ-PCR measuring of Ig/TCR rearrangements provides suitable sensitivity and specifi city, being, however, complicated by high costs of the assay, delayed purchasing of ASO, and loss of a gene target in rare cases. However, this method has been accepted in Europe as a standard approach to MRD monitoring [1].
Chimerism assays are used for assessing donor cell engraftment, but they also can be applied for relapse prediction. The study of chimerism by InDel-PCR has a sensitivity of 10-4 [30, 32], but up to 1% of the recipient cells, even after myeloablative conditioning, may be normally present in BM and PB aft er allo-HSCT [43, 44]. Th erefore, the sensitivity of donor chimerism for prediction of relapses is limited to 10-2.
Figure 5. Probability of relapse (A), OS (B) and EFS (C) in patients with ALL/biphenotypic AL according to MRD and chimerism after allo-HSCT. Curves are designated black (MRD-/no GVHD); blue (MRD-/aGVHD); red (MRD+/ no aGVHD); or green (MRD+/aGVHD)
In addition, the chimerism monitoring is a non-specific method, since the persistent residual cells of recipient origin can be either normal hematopoietic or malignant cells, or both.
MRD monitoring allows identifying the ALL patients being at high risk for relapses aft er alloHSCT. It was shown in ALL patients that the level of MRD before transplantation significantly aff ects the result of posttransplant outcome [4, 40, 45-52]. Not all patients with negative MRD pre-transplant remain relapse-free at later terms, as well as not all patients with positive MRD relapse aft er HSCT. Th erefore, the measurement of MRD post-HSCT is another powerful tool, with a potential for more precise relapse prediction. A limited number of trials has explored the role of MRD assays in the post-HSCT period [1]. Post-HSCT positive MRD strongly associated with high risk of relapse and low survival in childhood ALL [4, 40, 50, 52–55]. Th e presence of detectable MRD aft er transplant was independent of other factors, including pre-HCT MRD and aGVHD status [40].
In our study, the presence of MRD aft er allo-HSCT significantly increased the probability of disease recurrence and led to poor overall and event-free survival. We showed that the risk of relapse was increased only in the patients with high MRD levels (>10-3, CI of relapse is 100%), whereas risk of relapse did not diff er for the patients with MRD ≤10-3 and with negative MRD, (CI of relapse 11% and 15% accordingly). Similarly, Balduzzi et al. have shown that the patients who had high MRD >10-3 at any time point post-HSCT, did relapse, despite any attempts to prevent the recurrence of disease [54]. Most patients relapsed with MRD level of >10-3, but the patients with MRD <10-3-10-4 were more likely to clear their leukemia cells [52, 54, 56]. By contrast, the study of Bader et al. [53] has shown that any level of MRD aft er allo-HSCT did increase risk of relapse, even MRD <10-4 , if compared to MRD-free patients on D+60, +90 and +180, but not on +30 days, and the same results were reported by Zhao group [55]. However, our data and results from other authors [52-54, 56] suggest that the patients with low posttransplant MRD levels <10-3-10-4 do not necessarily relapse, and additional risk stratifi cation is needed.
Despite recommendations on monitoring of MRD and chimerism for relapse prediction of ALL aft er alloHSCT, there are only few studies comparing these two methods [20, 56, 57], and the results of these studies do not give a complete answer as to how a combination of these approaches can improve relapse prediction. We have obtained concordant results between MRD and chimerism in 74% cases. Standard methods for determining MPD are of >1lg10 more sensitive, than the methods for chimerism detection. Th e main diff erence between these two approaches is that MRD monitoring directly determines the residual tumor cells and the chimerism analysis gives only information about the persistence/ recoverye of autologous hematopoiesis. Reappearance of recipient cells may indicate the establishment of immunological tolerance thus potentially leading to a weaker immunological surveillance of malignant cells and the development of relapse [58]. Rarely, stable mixed chimerism in some patients with malignant diseases may persist for up to 20 years after alloHSCT, and it does not lead to relapse or rejection [59], although this is rather an exception to the rules. In the majority of cases, the onset of increasing mixed chimerism precedes disease recurrence [19, 20, 32, 60-62].
In our study, a combination of these two diagnostic approaches makes it possible to stratify patients into groups of high, intermediate and low risk of relapse with a very high accuracy. Th e most favorable group was presented by the patients with negative MRD and FDC with a good OS (94%) and EFS (75%), and a low incidence of relapse (12%). Th e presence of MRD combined with increasing MC led to the development of relapses in almost all patients (CI relapse 80%) and signifi cantly worse OS (20%) and EFS (0%). In the presence of FDC, some patients showed MRD clearance and became MRD-negative, but this group of patients still had relatively high risk of relapse (CI relapses 42%) and intermediate OS (44%) and EFS values (25%). Patients couldclear their MRD by an immunologic graft -versus-leukemia (GvL) eff ect, but MRD must be cleared until the establishment of graft tolerance towards the recipient; otherwise, uncontrolled proliferation of residual leukemia cell fi nally results in hematological relapse [54]. Th e patients with positive MRD in late posttransplant period are shown to relapse more readily, when compared to patients with MRD positivity over the fi rst 1-2 months [53-56]. During the initial phase aft er allo-HSCT (within the fi rst 2 months), immunologic reconstruction is incomplete, and GvL eff ect is not fully exhibited [55]. Our study also confi rms the theory of immunological tolerance, because MRD clearance was more often observed in patients with FDC and GvHD, or after DLI. None of the patients with positive MRD developed bone marrow relapse in the presence of GvHD, in contrast to patients with no GVHD (CI relapse 80%). The role of the GvL eff ect is supported by studies showing that the ALL patients who experience GvHD have a lower risk of relapse [40, 49, 56]. As a rule, these three parameters (MRD, GVHD and chimerism) are interrelated. Detection of MC was oft en combined with positive MRD and lack of GVHD. Absence or reduction of MRD was observed in the patients with FDC and GVHD development.
We have shown that the combination of MRD and chimerism monitoring allows stratifi cation of ALL patients into the groups of relapse risk. In contrast to previous studies [54, 56], we were able to fi nd out prognostic value of increasing MC due to application of sensitive PCR-based method of chimerism detection and testing of BM samples, along with PB cells. Our study demonstrates the combined eff ect of MRD, chimerism and GVHD on the outcomes in allo-HSCT patients. A serious issue is associated with development of extramedullary relapses which are underdiagnosed because they can manifest with no detectable MRD and in FDC state in the presence of GVHD, even in relapse burden [56, 63]. Th ere is also a risk to miss early signs of relapse, if the monitoring intervals for the marrow chimerism and MRD exceed 2 months. We recommend monitoring BM at least once or twice a month over fi rst 6-12 months aft er alloHSCT, when the risk of relapse is high, especially for the patients with previous positive MRD and/or MC, and absence of GVHD signs.
Like other workers, we observed that, in patients with MRD level of <10-3, the clearance of malignant clone can be achieved with preventive immunotherapy [54, 64]. In view of these considerations, MRD combined with chimerism could be used as a tool to guide posttransplant pre-emptive immunomodulation or immunotherapy, in order to prevent a disease relapse.
Conclusion
The presence of positive MRD aft er allo-HSCT is known to be an unfavorable prognostic factor associated with relapses, poor overall and decreased event-free survival. In patients with ALL, the presence of MRD aft er allo-HSCT is not always associated with development of relapses. The manifestation of the GvL eff ect can be observed in patients with FDC and GvHD or aft er DLI. Th e patients of a high-risk group for relapse include those with high MRD level >10-3, as well as the patients in whom the presence of MRD is combined with increasing mixed chimerism and/or absence of GVHD. Monitoring of MRD in bone marrow does not always allow
us to detect extramedullary relapses.
Acknowledgements
The authors report no confl icts of interest.
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Introduction
Allo-HSCT is a well-defined treatment mode for high-risk acute lymphoblastic leukemia (ALL) [1]. However, relapse still remains the major cause of treatment failure in children with ALL, even among patients who received transplantation during hematologic remission [2-4]. High risk of relapses aft er allo-HSCT arises, mostly, due to selection of the patients with signs of poor clinical prognosis (refractory to chemotherapy, unfavorable cytogenetic or molecular genetic alterations) [5, 6], whereas the patients with more favorable prognosis undergo standard chemotherapy treatment [1, 7]. Th e relapses occur in 30-35% of patients with ALL and it is one of the most common causes of mortality aft er allo-HSCT [2, 3, 8]. Survival of patients who experienced relapse is about 3-19% depending on the time between allo-HSCT and relapse [9]. In the case of clinical posttransplant relapse further treatment options are limited and often ineffective [10, 11]. For example, a second allo-HSCT can give a chance to cure such patients, but it is associated with high orbidity and mortality. Donor lymphocyte infusion (DLI) has a limited success if it is started during hematological relapse [12]. At the same time, immunotherapy at the stage of early relapse (before hematological manifestation), when the leukemia clone is still small, is more eff ective than relapse treatment [12-15]. Therefore, the study of early signs of disease recurrence is particularly important.
The early signs of impending ALL relapse aft er allo-HSCT are usually detected by MRD monitoring using the following means: 1) fl ow cytometry of leukemia-associated immunophenotype, or quantitative real-time PCR of chimeric oncogenes, or clonal rearrangements of immunoglobulin molecules, or T-cell receptor genes (Ig/TCR-PCR) [16-18]; 2) donor chimerism monitoring [19, 20].
A clone of ALL cells originating from a single primary-transformed cell carries identical Ig/TCR rearrangements in all the malignant cells. Th erefore, the rearrangements detected in ALL samples at diagnosis could serve as specifi c molecular markers for MRD monitoring. Ig/TCR rearrangements allow MRD monitoring in the vast majority of ALL patients, and comparing the results aft er allo-HSCT [21].
MRD monitoring in pediatric ALL by Ig/TCR rearrangements has widely been accepted as a reliable prognostic factor of relapse during chemotherapy and before allo-HSCT [1]. However, its application aft er allo-HSCT has been less clearly defi ned and still controversial. Th e signifi cance of precise quantifi cation of MRD aft er transplantation is not completely established. Th e aim of the study was to evaluate the impact of quantitative MRD on outcomes of allo-HSCT.
Patients and methods
Our study included 45 patients with ALL or biphenotypic AL who underwent the fi rst allo-HSCT at the Center for Pediatric Oncology, Hematology and Immunology from 2010 to 2017. Initial screening for Ig/TCR clonal rearrangements was performed in all the patients. MRD monitoring using Ig/TCR targets was performed in 35 of them (eight patients had no target markers, 1 had no primary engraft ment, no sample material was obtained aft er 1 alloHSCT). Basic characteristics of 35 patients with ALL/biphenotypic AL enrolled in the posttransplant MRD studies are listed in Table 1. The recipient age at the time of transplantation was 2-25 (median 11) years. All parents or guardians signed the informed consent. All the patients received myeloablative conditioning (MAC), except of one with Nijmegen syndrome/ALL who underwent a reduced-intensity conditioning regimen (RIC).
For MRD assays, bone marrow (BM) and peripheral blood (PB) samples were collected on days +30, +60, +100, +180, +365 aft er alloHSCT, and every six months thereaft er. Mononuclear BM cells were isolated in the Histopaque density gradient (Sigma-Aldrich, USA). DNA extraction was carried out by phenol-chloroform method. DNA quality and concentration was evaluated with a NanoDrop 2000c spectrophotometer (Th ermoFisher Scientifi c, USA).
Genomic DNA samples at diagnosis were screened by PCR for clonal IgH, IgK immunoglobulin and rearrangements of TCRD, TCRG, TCRB genes. DNA amplifi cation was performed with primers, recommended by BIOMED-1 Concerted Action [22] for IgK and TCRG genes, and a report by Chim et al. for IgH gene [23]. The TCRD gene was amplified according to Taube et al. [24], and TCRB by BIOMED-2 Concerted Action [21]. Further on, the specifi c PCR products were evaluated by heteroduplex analysis by polyacrylamide gel technique, then being cut from the gels, purifi ed and sequenced in the ABI PRISM 3130 Genetic Analyzer (Applied Biosystems, USA) in both directions. Detailed description of the detection procedure of diff erent Ig/TCR rearrangements in ALL was reported in our previous publications [25, 26]. Allele-specifi c oligonucleotides (ASO) primers were selected to cover the N region of rearrangement, specifi cally, for the 3’ end of primer. Secondary structures were avoided. At least two different ASO-primers were designed for each rearrangement point and tested, in order to choose the best system for MRD quantification.
Table 1. Characteristics of patients with ALL and biphenotypic AL (n= 35) included in the MRD study after allo-HSCT
ASO-primers and germline TaqMan probe approach were applied for RQ-PCR analysis in CFX96 machine (Bio-Rad, USA). PCR amplifi cation was performed in 20μL reaction mix with TaqMan Universal PCR Master Mix (Applied Biosystems, USA), 500 ng of genomic DNA, 500 ng of each primer and 150 ng of fl uorescent TaqMan probe labeled with 3’FAM, 5’BHQ. Th e panel of germline primers and probes was published elsewhere [27]. For MRD quantifi cation, we prepared serial ten-fold dilutions of diagnostic DNA in polyclonal controls to make a standard curve construction. To normalize the individual results, the same samples were amplifi ed with primers for albumin reference gene [28]. A standard curve for the albumin gene was plotted with diagnostic DNA serially diluted in water. Standard Quantity (SQ, mean of triplicate) was automatically generated by CFX96 based on standard curve for both albumin and target. Interpretation of MRD analysis results was performed in accordance with the guidelines published by the European Study Group on MRD detection [29].
RNA was isolated from the BM mononuclear cells with TRIzol reagent (Th ermo Fisher Scientifi c, USA). MRD monitoring based on measuring expression of chimeric oncogenes TEL-AML1, BCR-ABL1, MLL1-AF4 was performed by quantitative real-time PCR of the cDNA. Th e real-time PCR was performed in 25-μl volume containing 2x TaqMan Universal PCR Master Mix (Applied Biosystems, USA), 300 nM primers, 200 nM TaqMan probes and 5 μl of cDNA or standards. Commercial standards (Qiagen, Germany) were used for calibration of absolute gene copy numbers. The PCR conditions were as follows: 2 min, 50°C; 10 min, 95°C; 50 cycles (95°C, 15 sec; 60°C, 60 sec).
MRD detection was also performed by multiparametric fl ow cytometry (FC) of mononuclear cell suspensions (1 million cells/mL, 100 μl). A panel of monoclonal antibodies conjugated with fl uorescent labels FITC, PE, PC5, PC7 (Beckman Coulter, USA). In addition, we used reagents for fi xation and permeabilization (Becton Dickinson, USA) for detection of intracellular antigens. Following incubation and staining, the cells were washed once in phosphate buff er saline with subsequent fi xation in 1% paraformaldehyde. FC-analysis was carried out with the Navios fl ow cytofl uorimeter (Beckman Coulter, USA) using the CXP program.
Donor chimerism was determined by real-time PCR of InDel markers and multiplex PCR of short tandem repeats (STR) in BM and/or PB on +30, +45, +60, + 80, +100, +140, +180, +245, + 365 days aft er allo-HSCT and, thereaft er, every six months. In case of mixed chimerism (MC), the studies were conducted more oft en. AmpFlSTR® SGM Plus® PCR Amplification Kit (ABI, UK) was used for amplifi cation of STR markers, PCR products were separated by capillary electrophoresis using 3130 Genetic Analyzer (Applied Biosystems, USA). Distinct alleles were identifi ed by means of GeneMapper soft ware (Applied Biosystems, USA). InDel-PCR was performed as previously described [30-32]. Full donor chimerism (FDC) was defi ned as >99% donor cells, and mixed chimerism was accepted at 5-99% donor cells.
Statistical evaluation was performed by non-parametric methods using the STATISTICA approach. Overall survival was defi ned as the time period between allo-HSCT and death, or to the last observation date. Treatment-related mortality (TRM) was defi ned as a death in complete remission state (CR) without preceding relapse, from any causes associated with HSCT procedure. Event-free survival (EFS) was determined as survival without TRM, relapse, rejection, or secondary tumor. Th e time to clinical events (relapse, TRM, GVHD) was measured from the date of alloHSCT. Kaplan-Meier estimates were performed to predict probabilities for overall survival and EFS [33]. Th e log-rank test was used for comparisons. Cumulative incidence (CI) curves were calculated to assess incidence of relapse (CIR) and TRM [34]. Gray’s test was used for comparisons of CIs [35]. Fisher’s exact test was applied in order to compare the patients’ categorical data. Th e results of statistical evaluation were considered signifi cant at p<0.05.
Results
Survival of patients with different MRD status after allo-HSCT
Ig/TCR clonal rearrangements were identifi ed for 37 of 45 patients (82.2%). Chimeric oncogenes were determined only in 10 (22%) of 45 patients: 5 (11.1%) with MLL-AF4; 4 BCR-ABL1-positive cases (8.9%); one patient (2.2%) with TEL-AML1. MRD monitoring by Ig/TCR rearrangements was performed aft er 35 allo-HSCT that were included into the analysis. Th e median follow-up of the patients surviving aft er allo-HSCT was 3.6 years.
MRD status according to Ig/TCR target was negative in 21 (60%) patients, and only two of them (9.5%) relapsed. Positive MRD was detected in 14 (40%) patients, 7 (50%) of them had isolated bone marrow relapse. Th e three-year CI of relapse was higher in the patients with positive MRD at
any time aft er allo-HSCT (58.3±16.2%) as compared to the patients with negative MRD (10.7±7.4%), p=0.0042 (Fig. 1). Overall survival and EFS were signifi cantly lower in cases of positive MRD (33.2± 14.4% vs 83.6± 8.8%, p=0.008, and 18.9± 11.7% vs 66.6± 11.4%, p=0.002).
In all six patients who reached high MRD levels (>10-3), we observed recurrence of the disease. Only one (16.7%) patient relapsed of six children with intermediate MRD levels (10-4-10-3). Two patients with MDR level <10-4 retained their CR state. Generally, in cases of positive MRD, the patients with relapse showed higher levels of preceding MRD (1.6*10-1-2.7*10-4), than the relapse-free patients (<10-5-10-3), as seen from Table 2. The three-year cumulative incidence (CI) of relapse for the patients with non-detectable MRD, with MRD ≤10-3, and >10-3 was, respectively, 10.7±7.4% vs 14.6±14.6% vs 100% (p<0.0001). Overall survival rates (OS) were 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), and EFS rates were 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012), respectively (Fig. 2).
In two patients, positive MRD was not found in BM cells before relapse. One patient had extramedullary relapse (EMR) in the central nervous system (CNS). In the second patient, a loss of Ig/TCR target was observed in hematological BM relapse.
MRD monitoring with Ig/TCR rearrangements in BM, along with PB, was performed in 10 patients. In seven cases (70%), positive MRD was detected before relapse in both BM and PB. In three patients, MRD was detected in BM only, one of them relapsed. In this patient, MRD was still not detected in PB at the time of relapse.
Figure 1. Probability (CI) of relapse (A), OS (B) and EFS values (C) in the patients with ALL/biphenotypic AL according to MRD status after allo-HSCT
Figure 2. Probability (CI) of relapse (A), OS (B), and EFS (C) in patients with ALL/biphenotypic AL according to MRD levels after alloHSCT. Curves are designated black (MRD –); green (MRD >10-3); or red (MRD <10-3)
Comparison of MRD results obtained by different targets/methods
In nine patients, MRD was monitored by Ig/TCR rearrangements, as well as expression of BCR-ABL1 (n=4), MLL-AF4 (n=4), TEL-AML1 (n=1). In only one case, the results were discordant, i.e., the abovementioned patient who was negative by Ig/TCR target (loss of the target), but he was positive for MLL-AF4. In four patients, MRD was not detected, either by expression of BCR-ABL1 (n=2), MLL-AF4 (n=2), or Ig/TCR targets. Positive MRD was detected by both methods in four patients. Paired points for comparison were available in two patients. In one case, positive MRD was detectable by both approaches (MLL-AF4 and Ig/TCR markers). In another case (patient №12), we observed earlier appearance of MRD in BM as detected by TEL-AML expression (on day +98), than by Ig/TCR marker (detected at the next point of D+124). Hence, the fi rst method seems to be more sensitive (Fig. 3).
Table 2. Time dynamics of MDR in patients with ALL
Figure 3. MRD time course in Patient #12, according to TEL-AML expression and Ig/TCR rearrangement (Igk). Abscissa, gene copy number (log10); ordinate, terms posttransplant
MRD measured by immunophenotyping and Ig/TCR rearrangements was monitored in four patients in parallel (at the same time points aft er HSCT). Negative MRD was detected by both methods in one patient. In three patients, we received discordant results: there were positive MRD values of <10-3 detected by Ig/TCR gene rearrangements, however, being negative by immunophenotyping technique. Nevertheless, negative results were observed in some cases by both methods.
Comparison of MRD data obtained by Ig/TCR and chimerism markers
Donor chimerism monitoring was performed in all 35 patients.
1) Full donor chimerism (FDC) and negative MRD state were detected in 19 patients, only 2 of them have relapsed (Table 3). In one patient with loss of Ig/TCR target, a relapse was diagnosed more than 2 months aft er last chimerism monitoring in BM cells (D+377, late isolated BM relapse). Th e second patient with extramedullary CNS relapse had negative MRD and FDC in PB and BM cells, even at the time of relapse.
2) Mixed chimerism (MC) and negative MRD were detectable in 2 cases. One patient had negative MRD and MC (98.9%) in BM on D +30. Th is patient reached FDC (since +60 day), but died with infectious complications on D +542. Th e second patient showed FDC conversion to increasing MC accompanied by infection, and died on D +78.
3) FDC and positive MRD (up to 1.6*10-1) was observed in 7 patients, two of them have relapsed. Th e patient №12 had BM relapse on D +522, with last testing point at D +347, when full donor chimerism and MRD of 5*10-5 were determined. In the second patient (№13), a BM relapse was diagnosed by the D+226. Slightly decreased chimerism level of 99.1% was registered in blood leukocytes, along with increased MRD level to 15% at the last term before the relapse (D+197). In three patients with FDC, we observed MRD clearance, the rest of them retained their MRD positivity at the last examination.
Table 3. Comparison of MRD and chimerism monitoring data in ALL patients
4) MC and positive MRD was traced in seven patients, five of them had the disease recurrence. Before relapse, an increase of MC and MRD up to 2.2*10-2 was observed in four patients (the fi ft h patient had an early relapse, and only one monitoring point before relapse). Patient №5 with increasing MC has shown graft rejection on D +74 with subsequent autorecovery without ALL reoccurrence, with MRD levels in BM of <10-4 on days +27 to +39, then becoming negative at later terms. Patient №1 had an MC state (98.5% on D+30 in BM and PC) with FDC state achieved by the D +60; this patient is now alive, being in complete remission.
Thus, we have revealed suffi cient concordance between MRD and donor chimerism in 26 (74.3%) out of 35 cases. Th =e most favorable group comprised a subgroup with negative MRD and FDC, an intermediate group consisted of patients with positive MRD and FDC, and the most unfavorable group included the patients with positive MRD and increasing MC. Th e respective 3-year CI of relapse for these groups were as follows: 11.9 ± 8.2% vs 41.7 ± 29.5% vs 80.0 ± 23.9% (p<0.0008); the OS values were 94.4 ± 5.4% vs 44.4 ± 22.2% vs 20.0 ± 17.9% (p=0.0029); EFS probability was 75.0 ± 11.0% vs 25.0 ± 20.4% vs 0% (p<0.0001), respectively (Fig. 4).
Dependence of survival upon MRD and GVHD association
Grade I-IV acute GvHD (aGvHD) was observed in 17 (48.6%) of 35 patients, and six of them were diagnosed with severe aGvHD (grade III-IV). MRD-negative state was registered more oft en in the patients with aGvHD (in 13 of 17 cases), as compared to the GvHD-free cases (8 of 18 patients, p=0.085).
1) Among 13 patients with negative MRD and aGvHD, only 1 (7.7%) patient had relapse in CNS.
2) Among eight patients with negative MRD without aGvHD, nobody has relapsed.
3) None of the four patients with positive MRD and aGvHD relapsed. MRD clearance occurred in 4 patients (40%) on the days +100–+150.
4) In seven (70%) of 10 patients with positive MRD without aGvHD disease reoccurred. Four of these 10 patients received DLI, 2 of them experienced relapse despite GvHD signs observed aft er IDL.
Clinical outcomes of the patients with negative MRD without aGvHD, patients with negative MRD with aGvHD, and patients with positive MRD and aGvHD were nearly similar, being defi nitely better than in the group of aGvHD-free patients with positive MRD. Th e three-year CI of relapse rates were as follows: 20.0±20.0% vs 7.7±7.7% vs 0% vs 80.0±20.2% (p=0.008).Th e respective, overall survival probability was 80.0±17.9% vs 84.6±10.0% vs 66.7±27.2% vs 18.0±15.1% (p=0.026). Th e EFS values for these subgroups were: 60.1±21.9% vs 67.3±13.6% vs 66.7±27.2% vs 0% (p=0.0004), respectively (Fig. 5).
Figure 4. Probability of relapse (A), OS (B) and EFS (C) in patients with ALL/biphenotypic AL according to MRD and chimerism after allo-HSCT. Curves are designated black (MRD+/FDC); green (MRD+/FDC); or red (MRD-/ mixed chimerism increase)
Discussion
The MRD monitoring can help to identify presence of tumor cells that survived aft er the conditioning. However, this assay is applicable only for patients with a defi ned marker (chimeric oncogenes, mutations, Ig/TCR rearrangements or leukemia-associated immunophenotype). Identifi cation of tumor-specifi c mutations is the most accurate diagnostic approach showing high specifi city. However, the structure of these mutations should be suitable for MRD monitoring, with a sensitivity of, at least, 10-4 [36]. In ALL monitoring, quantitative real-time PCR (qPCR) allows to determine MRD by specifi c chimeric oncogenes/transcripts, point mutations and other rearrangements, such as BCR-ABL1, PML/ RARa, RUNX1-RUNX1T1 (AML1-ETO), CBFB-MYH11, MLL translocations, at a high sensitivity of 10-5-10-6 [37]. Chimeric oncogenes are detected only in a small number of patients with ALL [36, 38]. In our study, they were found only in 11% of transplantation patients. Th ere exists another alternative to chimeric oncogenes and mutations in ALL, i.e., clonal rearrangements of Ig and TCR genes, which are an attractive marker for MRD monitoring, being detectable in vast majority of ALL patients (up to 90-95% [36, 37], 82% of our patients).
Analytical sensitivity is an important aspect of MRD assay, since an arising leukemic clone posttransplant is regarded as an unfavorable event. MRD monitoring with Ig/TCR has a good sensitivity up to 10-4-10-5. Measurement of chimeric oncogene expression may be an even more sensitive approach in some cases, since a single malignant cell may contain several dozens or even thousands copies of chimeric oncogenes. It increases sensitivity up to 1 lg10, thus allowing earlier detection of tumor cells aft er allo-HSCT than with DNA-targets. However, the predictive value of individual methods and expression markers is not well defi ned. By contrast, MRD monitoring procedure with Ig/TCR rearrangements has been standardized and provides comparable results obtained from diff erent patients, which makes it possible to assess not only the presence of MDR aft er alloHSCT, but also takes its levels into account [4, 36, 37, 39]. Immunophenotyping using fl ow cytometry has a lower sensitivity (up to 10-4) than PCR-based methods. Its application for MRD monitoring aft er allo-HSCT is limited due to diffi culties with interpretation of results [40]. Bone marrow regeneration after allo-HSCT makes it diffi cult to identify leukemic cells on the background of normal lymphoid precursors [1].
It is also necessary to consider the stability of various MRD markers [36]. In rare cases, the Ig/TCR target can be lost due to somatic mutations accumulating in tumor cells [41, 42], what we have found in one case (2.9% of total group). RQ-PCR measuring of Ig/TCR rearrangements provides suitable sensitivity and specifi city, being, however, complicated by high costs of the assay, delayed purchasing of ASO, and loss of a gene target in rare cases. However, this method has been accepted in Europe as a standard approach to MRD monitoring [1].
Chimerism assays are used for assessing donor cell engraftment, but they also can be applied for relapse prediction. The study of chimerism by InDel-PCR has a sensitivity of 10-4 [30, 32], but up to 1% of the recipient cells, even after myeloablative conditioning, may be normally present in BM and PB aft er allo-HSCT [43, 44]. Th erefore, the sensitivity of donor chimerism for prediction of relapses is limited to 10-2.
Figure 5. Probability of relapse (A), OS (B) and EFS (C) in patients with ALL/biphenotypic AL according to MRD and chimerism after allo-HSCT. Curves are designated black (MRD-/no GVHD); blue (MRD-/aGVHD); red (MRD+/ no aGVHD); or green (MRD+/aGVHD)
In addition, the chimerism monitoring is a non-specific method, since the persistent residual cells of recipient origin can be either normal hematopoietic or malignant cells, or both.
MRD monitoring allows identifying the ALL patients being at high risk for relapses aft er alloHSCT. It was shown in ALL patients that the level of MRD before transplantation significantly aff ects the result of posttransplant outcome [4, 40, 45-52]. Not all patients with negative MRD pre-transplant remain relapse-free at later terms, as well as not all patients with positive MRD relapse aft er HSCT. Th erefore, the measurement of MRD post-HSCT is another powerful tool, with a potential for more precise relapse prediction. A limited number of trials has explored the role of MRD assays in the post-HSCT period [1]. Post-HSCT positive MRD strongly associated with high risk of relapse and low survival in childhood ALL [4, 40, 50, 52–55]. Th e presence of detectable MRD aft er transplant was independent of other factors, including pre-HCT MRD and aGVHD status [40].
In our study, the presence of MRD aft er allo-HSCT significantly increased the probability of disease recurrence and led to poor overall and event-free survival. We showed that the risk of relapse was increased only in the patients with high MRD levels (>10-3, CI of relapse is 100%), whereas risk of relapse did not diff er for the patients with MRD ≤10-3 and with negative MRD, (CI of relapse 11% and 15% accordingly). Similarly, Balduzzi et al. have shown that the patients who had high MRD >10-3 at any time point post-HSCT, did relapse, despite any attempts to prevent the recurrence of disease [54]. Most patients relapsed with MRD level of >10-3, but the patients with MRD <10-3-10-4 were more likely to clear their leukemia cells [52, 54, 56]. By contrast, the study of Bader et al. [53] has shown that any level of MRD aft er allo-HSCT did increase risk of relapse, even MRD <10-4 , if compared to MRD-free patients on D+60, +90 and +180, but not on +30 days, and the same results were reported by Zhao group [55]. However, our data and results from other authors [52-54, 56] suggest that the patients with low posttransplant MRD levels <10-3-10-4 do not necessarily relapse, and additional risk stratifi cation is needed.
Despite recommendations on monitoring of MRD and chimerism for relapse prediction of ALL aft er alloHSCT, there are only few studies comparing these two methods [20, 56, 57], and the results of these studies do not give a complete answer as to how a combination of these approaches can improve relapse prediction. We have obtained concordant results between MRD and chimerism in 74% cases. Standard methods for determining MPD are of >1lg10 more sensitive, than the methods for chimerism detection. Th e main diff erence between these two approaches is that MRD monitoring directly determines the residual tumor cells and the chimerism analysis gives only information about the persistence/ recoverye of autologous hematopoiesis. Reappearance of recipient cells may indicate the establishment of immunological tolerance thus potentially leading to a weaker immunological surveillance of malignant cells and the development of relapse [58]. Rarely, stable mixed chimerism in some patients with malignant diseases may persist for up to 20 years after alloHSCT, and it does not lead to relapse or rejection [59], although this is rather an exception to the rules. In the majority of cases, the onset of increasing mixed chimerism precedes disease recurrence [19, 20, 32, 60-62].
In our study, a combination of these two diagnostic approaches makes it possible to stratify patients into groups of high, intermediate and low risk of relapse with a very high accuracy. Th e most favorable group was presented by the patients with negative MRD and FDC with a good OS (94%) and EFS (75%), and a low incidence of relapse (12%). Th e presence of MRD combined with increasing MC led to the development of relapses in almost all patients (CI relapse 80%) and signifi cantly worse OS (20%) and EFS (0%). In the presence of FDC, some patients showed MRD clearance and became MRD-negative, but this group of patients still had relatively high risk of relapse (CI relapses 42%) and intermediate OS (44%) and EFS values (25%). Patients couldclear their MRD by an immunologic graft -versus-leukemia (GvL) eff ect, but MRD must be cleared until the establishment of graft tolerance towards the recipient; otherwise, uncontrolled proliferation of residual leukemia cell fi nally results in hematological relapse [54]. Th e patients with positive MRD in late posttransplant period are shown to relapse more readily, when compared to patients with MRD positivity over the fi rst 1-2 months [53-56]. During the initial phase aft er allo-HSCT (within the fi rst 2 months), immunologic reconstruction is incomplete, and GvL eff ect is not fully exhibited [55]. Our study also confi rms the theory of immunological tolerance, because MRD clearance was more often observed in patients with FDC and GvHD, or after DLI. None of the patients with positive MRD developed bone marrow relapse in the presence of GvHD, in contrast to patients with no GVHD (CI relapse 80%). The role of the GvL eff ect is supported by studies showing that the ALL patients who experience GvHD have a lower risk of relapse [40, 49, 56]. As a rule, these three parameters (MRD, GVHD and chimerism) are interrelated. Detection of MC was oft en combined with positive MRD and lack of GVHD. Absence or reduction of MRD was observed in the patients with FDC and GVHD development.
We have shown that the combination of MRD and chimerism monitoring allows stratifi cation of ALL patients into the groups of relapse risk. In contrast to previous studies [54, 56], we were able to fi nd out prognostic value of increasing MC due to application of sensitive PCR-based method of chimerism detection and testing of BM samples, along with PB cells. Our study demonstrates the combined eff ect of MRD, chimerism and GVHD on the outcomes in allo-HSCT patients. A serious issue is associated with development of extramedullary relapses which are underdiagnosed because they can manifest with no detectable MRD and in FDC state in the presence of GVHD, even in relapse burden [56, 63]. Th ere is also a risk to miss early signs of relapse, if the monitoring intervals for the marrow chimerism and MRD exceed 2 months. We recommend monitoring BM at least once or twice a month over fi rst 6-12 months aft er alloHSCT, when the risk of relapse is high, especially for the patients with previous positive MRD and/or MC, and absence of GVHD signs.
Like other workers, we observed that, in patients with MRD level of <10-3, the clearance of malignant clone can be achieved with preventive immunotherapy [54, 64]. In view of these considerations, MRD combined with chimerism could be used as a tool to guide posttransplant pre-emptive immunomodulation or immunotherapy, in order to prevent a disease relapse.
Conclusion
The presence of positive MRD aft er allo-HSCT is known to be an unfavorable prognostic factor associated with relapses, poor overall and decreased event-free survival. In patients with ALL, the presence of MRD aft er allo-HSCT is not always associated with development of relapses. The manifestation of the GvL eff ect can be observed in patients with FDC and GvHD or aft er DLI. Th e patients of a high-risk group for relapse include those with high MRD level >10-3, as well as the patients in whom the presence of MRD is combined with increasing mixed chimerism and/or absence of GVHD. Monitoring of MRD in bone marrow does not always allow
us to detect extramedullary relapses.
Acknowledgements
The authors report no confl icts of interest.
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2 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Российская Федерация
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20888" ["VALUE"]=> array(2) { ["TEXT"]=> string(3918) "<p style="text-align: justify;"> Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов. </p> <h2 style="text-align: justify;">Выводы</h2> <p style="text-align: justify;"> Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3752) "
Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.
Пациенты и методы
Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.
Выводы
Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.
Ключевые слова
Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.
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2 R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20892" ["VALUE"]=> array(2) { ["TEXT"]=> string(2321) "<p style="text-align: justify;"> At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes<br> aft er allo-HSCT. </p> <h2 style="text-align: justify;">Patients and methods</h2> <p style="text-align: justify;"> The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2145) "
At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes
aft er allo-HSCT.
Patients and methods
The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.
Conclusion
Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.
Keywords
Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.
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Lavrinenko <sup>1</sup>, Alexandr N. Meleshko <sup>1</sup>, Dmitry V. Lutskovich <sup>1</sup>, Yulia E. Mareiko <sup>1</sup>, Dmitriy V. Prudnikov <sup>1</sup>, Mikhail V. Belevtsev <sup>1</sup>, Olga V. Aleynikova <sup>1</sup>, Ildar M. Barkhatov <sup>2</sup>, Boris V. Afanasyev <sup>2</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(309) "Victoria A. Lavrinenko 1, Alexandr N. Meleshko 1, Dmitry V. Lutskovich 1, Yulia E. Mareiko 1, Dmitriy V. Prudnikov 1, Mikhail V. Belevtsev 1, Olga V. Aleynikova 1, Ildar M. Barkhatov 2, Boris V. Afanasyev 2" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(309) "Victoria A. Lavrinenko 1, Alexandr N. Meleshko 1, Dmitry V. Lutskovich 1, Yulia E. Mareiko 1, Dmitriy V. Prudnikov 1, Mikhail V. Belevtsev 1, Olga V. Aleynikova 1, Ildar M. Barkhatov 2, Boris V. Afanasyev 2
" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20892" ["VALUE"]=> array(2) { ["TEXT"]=> string(2321) "<p style="text-align: justify;"> At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes<br> aft er allo-HSCT. </p> <h2 style="text-align: justify;">Patients and methods</h2> <p style="text-align: justify;"> The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2145) "
At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes
aft er allo-HSCT.
Patients and methods
The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.
Conclusion
Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.
Keywords
Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2145) "
At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes
aft er allo-HSCT.
Patients and methods
The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.
Conclusion
Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.
Keywords
Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.
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Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(348) "1 Th e Republican Research and Practical Center of Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus2 R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(348) "1 Th e Republican Research and Practical Center of Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus
2 R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20886" ["VALUE"]=> array(2) { ["TEXT"]=> string(562) "Виктория А. Лавриненко <sup>1</sup>, Александр Н. Мелешко <sup>1</sup>, Дмитрий В. Луцкович <sup>1</sup>, Юлия Е. Марейко <sup>1</sup>, Дмитрий В. Прудников <sup>1</sup>, Михаил В. Белевцев <sup>1</sup>, Ольга В. Алейникова <sup>1</sup>, Ильдар М. Бархатов <sup>2</sup>, Борис В. Афанасьев <sup>2</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(448) "Виктория А. Лавриненко 1, Александр Н. Мелешко 1, Дмитрий В. Луцкович 1, Юлия Е. Марейко 1, Дмитрий В. Прудников 1, Михаил В. Белевцев 1, Ольга В. Алейникова 1, Ильдар М. Бархатов 2, Борис В. Афанасьев 2
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(448) "Виктория А. Лавриненко 1, Александр Н. Мелешко 1, Дмитрий В. Луцкович 1, Юлия Е. Марейко 1, Дмитрий В. Прудников 1, Михаил В. Белевцев 1, Ольга В. Алейникова 1, Ильдар М. Бархатов 2, Борис В. Афанасьев 2
" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20888" ["VALUE"]=> array(2) { ["TEXT"]=> string(3918) "<p style="text-align: justify;"> Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК. </p> <h2 style="text-align: justify;">Пациенты и методы</h2> <p style="text-align: justify;"> Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов. </p> <h2 style="text-align: justify;">Выводы</h2> <p style="text-align: justify;"> Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3752) "
Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.
Пациенты и методы
Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.
Выводы
Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.
Ключевые слова
Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.
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Пациенты и методы
Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.
Выводы
Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.
Ключевые слова
Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.
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Introduction
Renal transplantation is considered the best treatment modality for end-stage renal disease (ESRD), off ering better survival than chronic hemodialysis. Yet, posttransplant malignancy is considered the second cause of death in renal transplant patients aft er cardiovascular diseases. Acquired immune defi ciency caused by immunosuppressive drugs is supposed of being the cause of such high incidence. Th e most common malignancy in those patients is non-melanocytic skin cancer, while thyroid cancer is not very common and does not show a higher incidence than in general population [1-4].
Case presentation
T e patient was a fift y-three year-old male, diabetic and hypertensive, married with two off springs. He had a history of renal transplantation in April, 2004 from a living donor aft er suff ering from end-stage renal disease (ESRD) secondary to hypertension. He was kept on immunosuppressant therapy, received cyclosporine (100 mg daily dose) for 11 years (2004- 2015), followed by sirolimus (1 mg daily) for 3 years (2015 till now). He has been receiving daily doses of prednisone (10 mg) and azathioprine (100 mg) from 2004 till now.
The patient had history of prior excision of right pre-auricular lesion in 2015, with histologically proven keratoacanthoma, followed aft er 6 months by wide local excision of a recurrent tumor at the same site with postoperative pathology revealing grade I squamous cell carcinoma (SCC, a primary malignancy), with free all safety margins from tumor tissue.
He was presented to our center in February 2017 complaining from right pre-auricular ulcer. Physical examination revealed good general condition with right pre-auricular ulcer, with raised everted edges, necrotic base and purulent discharge. Sonography of the neck region revealed enlarged distorted intraparotid lymph nodes, as well as an incidentally discovered left solitary thyroid nodule 1.5x1.1 cm in size, the nodule was solid, iso-echoic with calcifi cation foci, and with poorly defi ned outline, thus being classifi ed as TIRADS 5 nodule. Computed tomography (CT) examination revealed a soft tissue swelling invading the skin and involving superficial lobe of the right parotid gland measuring 3x2x1 cm. CT showed also two suspicious left cervical lymph nodes (LNs), the largest was 10x9x8 mm.
The patient underwent wide local excision of the tumor en bloc with superficial lobe of the right parotid gland, ipsilateral modifi ed radical block neck dissection, as well as left hemithyroidectomy from which frozen sections were examined, showing no evidence for malignancy. Paraffin sections prepared from the surgical specimens revealed malignant tumor proliferation formed of malignant squamoid epithelial cell foci with frequent central keratin pearls separated by desmoplastic infl ammatory stroma. Th e cells showed moderate pleomorphism, abundant eosinophilic cytoplasm, vesicular nuclei and prominent nucleoli. Th e tumor was seen to infi ltrate adjacent parotid gland, and one of three intraparotid lymph nodes, with all twenty-seven lateral LNs being unaff ected, leading to the diagnosis of pre-auricular grade I SCC infi ltrating parotid gland, with tumor-negative lateral lymph nodes. (Fig. 1). Histological sections prepared from left thyroid lobe revealed multiple nodules showing malignant tumoral proliferation consisting of papillary structures lined by cuboidal epithelial cells showing nuclear overlapping, washing out and grooving with coff ee bean appearance, thus leading to the fi nal diagnosis of papillary thyroid carcinoma (Second malignancy, Fig. 2). Two weeks later, the patient underwent completion thyroidectomy and contralateral selective block neck dissection (levels II-V) which revealed a hyperplastic thyroid nodule and a single positive lateral lymph node infiltrated by papillary thyroid carcinoma.
He was referred to Clinical Oncology Department for further management. In view of renal transplantation history, only one positive LN and that the patient was obsessive about nephrotoxic drugs, radioactive iodine was omitted, and the decision was to receive suppressive dose of L-thyroxine and radiotherapy on the SCC tumor bed.
Eight months later, the patient was presented with right thumb lesion. Histopatholigical examination of the biopsy showed pseudoepitheliomatous hyperplasia. Yet, wide local excision of the lesion with microscopic examination of the specimen described malignant tumoral proliferation formed of sheets and nests of malignant squamous epithelium showing moderate atypia and pleomorphism with focal central keratin pearls and dyskeratosis, thus leading to the diagnosis of grade II squamous cell carcinoma with free all safety margins from tumor tissue (Third malignancy, Fig. 3). Nine months later, he suff ered from local recurrence in his right thumb for which he underwent thumb amputation with free surgical margin.
Discussion
Renal transplantation is considered the best treatment modality for patients with end-stage renal disease (ESRD) who are candidates for transplantation, with routine use of immunosuppressive therapy to prevent graft rejection. Th is makes transplantation not only a life-saving procedure, but also a life-changing one. Th e use of immunosuppressants led to increasing the risk for developing malignancy by about three- to four-fold compared to general population, with a reported incidence of 4-18%. Th e transplanted patients are considered having higher risk for both incidence and mortality from cancer, being the second leading cause of death aft er cardiovascular diseases in this cohort. Th is is usually explained by lacking immunity surveillance allowing potentially neoplastic cells to proliferate due to opportunistic oncogenic viral infections or somatic mutations, DNA damage, increased age of transplanted population, more biologically aggressive tumors, as well as using less aggressive cancer treatment modalities, concerns for suppressed immunity and higher risk of graft rejection. Eventually, some of the immunosuppressive drugs are reported to have pro-carcinogenic properties. The most common malignancies among renal transplant patients are a non-melanocytic skin cancer followed by Kaposi sarcoma. Most of them are de novo malignancies rather than those recurrent of pre-transplant malignancy, or donor-derived tumors. The incidence of cancer is increased by the duration of immunosuppressive therapy and use of steroids [5-14]. Despite the developing malignancy does not aff ect graft survival, the reduction of malignancy risk among transplant patients is very important since they experience worse outcomes with increased cancer-related mortality. Th is may be achieved by using immunosuppressive drugs with antitumor eff ects or adopting low-level immunosuppression as well as regular cancer screening of the transplanted patients [1, 9, 15]. Specifi c cancer prevention, screening and treatment programs for people with solid organ transplantation are highly recommended [4, 13].
Once diagnosis of posttransplant malignancy is established, the adequate oncological management of the disease, as well as modulation of immunosuppressants should be performed, including dose reduction, withdrawal, or drug substitution, e.g., based on mammalian target of rapamycin (mTOR) inhibition. Their application is shown to be associated even with regression in non-metastatic malignancies [16, 17].
Non-melanocytic skin cancer (NMSC) is the most common malignancy in solid organ transplant patients and, especially, in renal transplant patients, with a 65-250-fold increased incidence risk. Squamous cell carcinoma is the most common NMSC type, followed by basal cell carcinoma with an incidence ratio 4:1, thus being diff erent from general population where basal cell carcinoma is more common. Besides being more aggressive, it tends to be presented in multiple sites after the initial lesion. Th e risk for developing SCC is higher in light-colored skin people and those with long-term immunosuppression with tendency for multiplicity in the sun-exposed areas and higher risk for recurrence [11]. Thyroid cancer aft er renal transplantation shows non-significant higher incidence which may be explained by the use of immunosuppressive drugs, as well as routine diagnostics by performance of neck ultrasonography, due to associated hyperparathyroidism in ESRD patients. However, its incidence is increased in ESRD patients who did not undergo transplantation as well. Th yroid cancer in renal transplant patients shows the same prognosis and rate of recurrence as for general population, despite showing diff erent gender distribution. These patients are advised to be treated with the same modalities as other thyroid cancer patients [2, 10].
Conclusion
Incidence of posttransplant malignancy secondary to immunosuppression is a common event, being the second leading cause of death for such patients. Non-melanocytic skin cancer is the most common malignancy aft er renal transplantation. Malignancy risk reduction among transplant patients is a must even if malignancy is not associated with worse graft outcome. Specifi c cancer prevention, screening and treatment programs for those people are highly recommended.
Conflict of interest
None declared.
References
1. Choi SJ, Choi D, Kwon OJ. Incidence of post-transplant malignancy aft er renal transplantation: single center analysis. J Korean Soc Transpl [Internet]. Th e Korean Society for Transplantation; 2014;28(4):204-210.
2. Kluijfh out WP, Drake FT, Pasternak JD, Beninato T, Mitmaker EJ, Gosnell JE, et al. De novo thyroid cancer following solid organ transplantation – A 25-year experience at a high-volume institution with a review of the literature. J Surg Oncol. 2017 Feb 1;115(2):105-108.
3. Wahab KA, Attia E, Arafa M, Sorogy M El, Wahab MA. Micro-invasive papillary thyroid lesion in a post living donor liver transplant patient: A case report. Int J Case Reports Images. 2016;7(5):323-326.
4. Zhang J, Ma L, Xie Z, Guo Y, Sun W, Zhang L, et al. Epidemiology of post-transplant malignancy in Chinese renal transplant recipients: a single-center experience and literature review. Med Oncol. 2014;31(7):32.
5. Engberg H, Wehberg S, Bistrup C, Heaf J, Sørensen SS, Th iesson HC, et al. Cancer risk and mortality aft er kidney transplantation: a population-based study on diff erences between Danish centres using standard immunosuppression with and without glucocorticoids. Nephrol Dial Transplant. 2016;31(12):2149-2156.
6. Asch WS, Perazella MA. Cancer and mortality in solid-organ transplantation: preventable or inevitable? Am J Kidney Dis. Elsevier; 2018;68(6):839-842.
7. Wong G, Au E, Badve S V, Lim WH. Breast Cancer and Transplantation. Am J Transplant. 2017;17(9):2243-2253.
8. Tanaka T, Voigt MD. Decision tree analysis to stratify risk of de novo non-melanoma skin cancer following liver transplantation. J Cancer Res Clin Oncol. 2018;144(3):607-615.
9. Pendón-Ruiz de Mier V, Navarro Cabello MD, Martínez Vaquera S, Lopez-Andreu M, Aguera Morales ML, Rodriguez- Benot A, et al. Incidence and long-term prognosis of cancer aft er kidney transplantation. Transplant Proc. Elsevier; 2018;47(9):2618-2621.
10. Lee J, Jeong JJ, Lee YS, Nam KH, Chang HS, Chung WY, et al. Incidence and Clinical behavior of papillary thyroid carcinoma in renal allograft recipients: A single center experience. Transplant Proc. Elsevier; 2008;40(10):3751-3754.
11. Amre R, Michel RP. Transplantation and Malignancy BT – Pathology of Transplantation: A Practical Diagnostic Approach. In: Michel RP, Berry GJ, editors. Cham: Springer International Publishing; 2016. p. 451-476.
12. Gao PJ, Gao J, Li Z, Hu ZP, Zhu JY. De novo malignancy aft er liver transplantation: a single-center experience of 14 cases. Ann Surg Treat Res. 2015;88(4):222–228.
13. Sa A, Ka F, Daly C, et. al. Cancer mortality among recipients of solid-organ transplantation in ontario, canada. JAMA Oncol. 2016;2(4):463-469.
14. Miyazaki T, Sato S, Kondo T, Kusaka M, Gotoh M, Saiki Y, et al. National survey of de novo malignancy aft er solid organ transplantation in Japan. Surg Today. 2018; Available from: https://doi.org/10.1007/s00595-018-1628-9 15. Acuna SA, Huang JW, Dossa F, Shah PS, Kim SJ, Baxter NN. Cancer recurrence aft er solid organ transplantation: A systematic review and meta-analysis. Transplant Rev. 2017;31(4):240-248.
16. Rama I, Grinyó JM. Malignancy aft er renal transplantation: the role of immunosuppression. Nat Rev Nephrol 2010;6:511.
17. Manuelli M, De Luca L, Iaria G, Tatangelo P, Sforza D, Perrone L, et al. Conversion to rapamycin immunosuppression for malignancy aft er kidney transplantation. Transplant Proc. 2010;42(4):1314-1316.
Introduction
Renal transplantation is considered the best treatment modality for end-stage renal disease (ESRD), off ering better survival than chronic hemodialysis. Yet, posttransplant malignancy is considered the second cause of death in renal transplant patients aft er cardiovascular diseases. Acquired immune defi ciency caused by immunosuppressive drugs is supposed of being the cause of such high incidence. Th e most common malignancy in those patients is non-melanocytic skin cancer, while thyroid cancer is not very common and does not show a higher incidence than in general population [1-4].
Case presentation
T e patient was a fift y-three year-old male, diabetic and hypertensive, married with two off springs. He had a history of renal transplantation in April, 2004 from a living donor aft er suff ering from end-stage renal disease (ESRD) secondary to hypertension. He was kept on immunosuppressant therapy, received cyclosporine (100 mg daily dose) for 11 years (2004- 2015), followed by sirolimus (1 mg daily) for 3 years (2015 till now). He has been receiving daily doses of prednisone (10 mg) and azathioprine (100 mg) from 2004 till now.
The patient had history of prior excision of right pre-auricular lesion in 2015, with histologically proven keratoacanthoma, followed aft er 6 months by wide local excision of a recurrent tumor at the same site with postoperative pathology revealing grade I squamous cell carcinoma (SCC, a primary malignancy), with free all safety margins from tumor tissue.
He was presented to our center in February 2017 complaining from right pre-auricular ulcer. Physical examination revealed good general condition with right pre-auricular ulcer, with raised everted edges, necrotic base and purulent discharge. Sonography of the neck region revealed enlarged distorted intraparotid lymph nodes, as well as an incidentally discovered left solitary thyroid nodule 1.5x1.1 cm in size, the nodule was solid, iso-echoic with calcifi cation foci, and with poorly defi ned outline, thus being classifi ed as TIRADS 5 nodule. Computed tomography (CT) examination revealed a soft tissue swelling invading the skin and involving superficial lobe of the right parotid gland measuring 3x2x1 cm. CT showed also two suspicious left cervical lymph nodes (LNs), the largest was 10x9x8 mm.
The patient underwent wide local excision of the tumor en bloc with superficial lobe of the right parotid gland, ipsilateral modifi ed radical block neck dissection, as well as left hemithyroidectomy from which frozen sections were examined, showing no evidence for malignancy. Paraffin sections prepared from the surgical specimens revealed malignant tumor proliferation formed of malignant squamoid epithelial cell foci with frequent central keratin pearls separated by desmoplastic infl ammatory stroma. Th e cells showed moderate pleomorphism, abundant eosinophilic cytoplasm, vesicular nuclei and prominent nucleoli. Th e tumor was seen to infi ltrate adjacent parotid gland, and one of three intraparotid lymph nodes, with all twenty-seven lateral LNs being unaff ected, leading to the diagnosis of pre-auricular grade I SCC infi ltrating parotid gland, with tumor-negative lateral lymph nodes. (Fig. 1). Histological sections prepared from left thyroid lobe revealed multiple nodules showing malignant tumoral proliferation consisting of papillary structures lined by cuboidal epithelial cells showing nuclear overlapping, washing out and grooving with coff ee bean appearance, thus leading to the fi nal diagnosis of papillary thyroid carcinoma (Second malignancy, Fig. 2). Two weeks later, the patient underwent completion thyroidectomy and contralateral selective block neck dissection (levels II-V) which revealed a hyperplastic thyroid nodule and a single positive lateral lymph node infiltrated by papillary thyroid carcinoma.
He was referred to Clinical Oncology Department for further management. In view of renal transplantation history, only one positive LN and that the patient was obsessive about nephrotoxic drugs, radioactive iodine was omitted, and the decision was to receive suppressive dose of L-thyroxine and radiotherapy on the SCC tumor bed.
Eight months later, the patient was presented with right thumb lesion. Histopatholigical examination of the biopsy showed pseudoepitheliomatous hyperplasia. Yet, wide local excision of the lesion with microscopic examination of the specimen described malignant tumoral proliferation formed of sheets and nests of malignant squamous epithelium showing moderate atypia and pleomorphism with focal central keratin pearls and dyskeratosis, thus leading to the diagnosis of grade II squamous cell carcinoma with free all safety margins from tumor tissue (Third malignancy, Fig. 3). Nine months later, he suff ered from local recurrence in his right thumb for which he underwent thumb amputation with free surgical margin.
Discussion
Renal transplantation is considered the best treatment modality for patients with end-stage renal disease (ESRD) who are candidates for transplantation, with routine use of immunosuppressive therapy to prevent graft rejection. Th is makes transplantation not only a life-saving procedure, but also a life-changing one. Th e use of immunosuppressants led to increasing the risk for developing malignancy by about three- to four-fold compared to general population, with a reported incidence of 4-18%. Th e transplanted patients are considered having higher risk for both incidence and mortality from cancer, being the second leading cause of death aft er cardiovascular diseases in this cohort. Th is is usually explained by lacking immunity surveillance allowing potentially neoplastic cells to proliferate due to opportunistic oncogenic viral infections or somatic mutations, DNA damage, increased age of transplanted population, more biologically aggressive tumors, as well as using less aggressive cancer treatment modalities, concerns for suppressed immunity and higher risk of graft rejection. Eventually, some of the immunosuppressive drugs are reported to have pro-carcinogenic properties. The most common malignancies among renal transplant patients are a non-melanocytic skin cancer followed by Kaposi sarcoma. Most of them are de novo malignancies rather than those recurrent of pre-transplant malignancy, or donor-derived tumors. The incidence of cancer is increased by the duration of immunosuppressive therapy and use of steroids [5-14]. Despite the developing malignancy does not aff ect graft survival, the reduction of malignancy risk among transplant patients is very important since they experience worse outcomes with increased cancer-related mortality. Th is may be achieved by using immunosuppressive drugs with antitumor eff ects or adopting low-level immunosuppression as well as regular cancer screening of the transplanted patients [1, 9, 15]. Specifi c cancer prevention, screening and treatment programs for people with solid organ transplantation are highly recommended [4, 13].
Once diagnosis of posttransplant malignancy is established, the adequate oncological management of the disease, as well as modulation of immunosuppressants should be performed, including dose reduction, withdrawal, or drug substitution, e.g., based on mammalian target of rapamycin (mTOR) inhibition. Their application is shown to be associated even with regression in non-metastatic malignancies [16, 17].
Non-melanocytic skin cancer (NMSC) is the most common malignancy in solid organ transplant patients and, especially, in renal transplant patients, with a 65-250-fold increased incidence risk. Squamous cell carcinoma is the most common NMSC type, followed by basal cell carcinoma with an incidence ratio 4:1, thus being diff erent from general population where basal cell carcinoma is more common. Besides being more aggressive, it tends to be presented in multiple sites after the initial lesion. Th e risk for developing SCC is higher in light-colored skin people and those with long-term immunosuppression with tendency for multiplicity in the sun-exposed areas and higher risk for recurrence [11]. Thyroid cancer aft er renal transplantation shows non-significant higher incidence which may be explained by the use of immunosuppressive drugs, as well as routine diagnostics by performance of neck ultrasonography, due to associated hyperparathyroidism in ESRD patients. However, its incidence is increased in ESRD patients who did not undergo transplantation as well. Th yroid cancer in renal transplant patients shows the same prognosis and rate of recurrence as for general population, despite showing diff erent gender distribution. These patients are advised to be treated with the same modalities as other thyroid cancer patients [2, 10].
Conclusion
Incidence of posttransplant malignancy secondary to immunosuppression is a common event, being the second leading cause of death for such patients. Non-melanocytic skin cancer is the most common malignancy aft er renal transplantation. Malignancy risk reduction among transplant patients is a must even if malignancy is not associated with worse graft outcome. Specifi c cancer prevention, screening and treatment programs for those people are highly recommended.
Conflict of interest
None declared.
References
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Вторичные злокачественные новообразования после трансплантации почек являются нередкими событиями. В этом сообщении мы рассматриваем одну из причин посттрансплантационной смертности. Сообщается о клиническом случае трансплантации почек с последующей иммуносупрессивной терапией и развитием через 11 лет синхронного плоскоклеточного рака кожи и папиллярной карциномы щитовидной железы, которые диагностировали и лечили в онкологическом центре университета Мансура.
Ключевые слова
Трансплантация почек, иммуносупрессивные препараты, синхронные злокачественные опухоли.
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In this report we considered one of the causes of posttransplant mortality. We report a renal transplant case and immune suppression treatment followed 11 years later by synchronous skin squamous cell carcinoma and papillary thyroid carcinoma that was diagnosed, presented and managed at the Oncology Center at Mansoura University. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Kidney transplantation, immunosuppressive drugs, synchronous malignancy. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(619) "Secondary malignancies following renal transplantation are not an uncommon event. In this report we considered one of the causes of posttransplant mortality. 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Keywords
Kidney transplantation, immunosuppressive drugs, synchronous malignancy.
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Shebl 2" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20900" ["VALUE"]=> array(2) { ["TEXT"]=> string(685) "<p style="text-align: justify;"> Secondary malignancies following renal transplantation are not an uncommon event. In this report we considered one of the causes of posttransplant mortality. We report a renal transplant case and immune suppression treatment followed 11 years later by synchronous skin squamous cell carcinoma and papillary thyroid carcinoma that was diagnosed, presented and managed at the Oncology Center at Mansoura University. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Kidney transplantation, immunosuppressive drugs, synchronous malignancy. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(619) "Secondary malignancies following renal transplantation are not an uncommon event. In this report we considered one of the causes of posttransplant mortality. We report a renal transplant case and immune suppression treatment followed 11 years later by synchronous skin squamous cell carcinoma and papillary thyroid carcinoma that was diagnosed, presented and managed at the Oncology Center at Mansoura University.
Keywords
Kidney transplantation, immunosuppressive drugs, synchronous malignancy.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(619) "Secondary malignancies following renal transplantation are not an uncommon event. In this report we considered one of the causes of posttransplant mortality. We report a renal transplant case and immune suppression treatment followed 11 years later by synchronous skin squamous cell carcinoma and papillary thyroid carcinoma that was diagnosed, presented and managed at the Oncology Center at Mansoura University.
Keywords
Kidney transplantation, immunosuppressive drugs, synchronous malignancy.
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Салех <sup>1</sup>, Абдальхади М. Шебль <sup>2</sup>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(194) "Омар Хамди 1, Сара Раафат 2, Амр Абузид 1, Махмуд М. Салех 1, Абдальхади М. Шебль 2" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(194) "Омар Хамди 1, Сара Раафат 2, Амр Абузид 1, Махмуд М. Салех 1, Абдальхади М. Шебль 2" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20896" ["VALUE"]=> array(2) { ["TEXT"]=> string(1253) "<p style="text-align: justify;"> Вторичные злокачественные новообразования после трансплантации почек являются нередкими событиями. В этом сообщении мы рассматриваем одну из причин посттрансплантационной смертности. Сообщается о клиническом случае трансплантации почек с последующей иммуносупрессивной терапией и развитием через 11 лет синхронного плоскоклеточного рака кожи и папиллярной карциномы щитовидной железы, которые диагностировали и лечили в онкологическом центре университета Мансура. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация почек, иммуносупрессивные препараты, синхронные злокачественные опухоли. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1187) "Вторичные злокачественные новообразования после трансплантации почек являются нередкими событиями. В этом сообщении мы рассматриваем одну из причин посттрансплантационной смертности. Сообщается о клиническом случае трансплантации почек с последующей иммуносупрессивной терапией и развитием через 11 лет синхронного плоскоклеточного рака кожи и папиллярной карциномы щитовидной железы, которые диагностировали и лечили в онкологическом центре университета Мансура.
Ключевые слова
Трансплантация почек, иммуносупрессивные препараты, синхронные злокачественные опухоли.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1187) "Вторичные злокачественные новообразования после трансплантации почек являются нередкими событиями. В этом сообщении мы рассматриваем одну из причин посттрансплантационной смертности. Сообщается о клиническом случае трансплантации почек с последующей иммуносупрессивной терапией и развитием через 11 лет синхронного плоскоклеточного рака кожи и папиллярной карциномы щитовидной железы, которые диагностировали и лечили в онкологическом центре университета Мансура.
Ключевые слова
Трансплантация почек, иммуносупрессивные препараты, синхронные злокачественные опухоли.
" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20895" ["VALUE"]=> array(2) { ["TEXT"]=> string(351) "<sup>1</sup> Отделение хирургической онкологии, онкологический центр университета Мансура <sup>2</sup> Отделение патологической анатомии, Факультет медицины, университет Мансура, Египет" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(327) "1 Отделение хирургической онкологии, онкологический центр университета Мансура 2 Отделение патологической анатомии, Факультет медицины, университет Мансура, Египет" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(327) "1 Отделение хирургической онкологии, онкологический центр университета Мансура 2 Отделение патологической анатомии, Факультет медицины, университет Мансура, Египет" } } } [7]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "117" ["~IBLOCK_SECTION_ID"]=> string(3) "117" ["ID"]=> string(4) "1612" ["~ID"]=> string(4) "1612" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(214) "Сравнительный анализ методов секвенирования NGS и по Сэнгеру при HLA-типировании в российской университетской клинике" ["~NAME"]=> string(214) "Сравнительный анализ методов секвенирования NGS и по Сэнгеру при HLA-типировании в российской университетской клинике" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(22) "02/06/2019 11:12:10 pm" ["~TIMESTAMP_X"]=> string(22) "02/06/2019 11:12:10 pm" ["DETAIL_PAGE_URL"]=> string(158) "/en/archive/tom-7-nomer-4/eksperimentalnye-issledovaniya/sravnitelnyy-analiz-metodov-sekvenirovaniya-ngs-i-po-sengeru-pri-hla-tipirovanii-v-rossiyskoy-univer/" ["~DETAIL_PAGE_URL"]=> string(158) "/en/archive/tom-7-nomer-4/eksperimentalnye-issledovaniya/sravnitelnyy-analiz-metodov-sekvenirovaniya-ngs-i-po-sengeru-pri-hla-tipirovanii-v-rossiyskoy-univer/" ["LIST_PAGE_URL"]=> string(12) "/en/archive/" ["~LIST_PAGE_URL"]=> string(12) "/en/archive/" ["DETAIL_TEXT"]=> string(25297) "Introduction
The Major Histocompatibility Complex (MHC) is among the most polymorphic genetic systems in humans. Over last decade, extensive research in HLA (Human Leukocyte Antigens) has revealed hundreds of new HLA alleles through intensive application of immunogenetic sequencing methods, including monoallelic Sanger-sequencing method, or, more recently, next-generation sequencing. In September 2018, the database of the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System (IPD-IMGT/HLA Database) contained information on the nucleotide sequences of 20272 diff erent HLA alleles, of which 14800 were HLA class I and 5288 founded for the HLA class II alleles [1-3].
During last 20 years, the automated Sanger technique has become a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening required some novel technologies of multiplex DNA sequencing. It depicts these modern methods as the second-generation approaches (Next-Generation Sequencing, NGS). Th ese technological platforms based on diff erent strategies, regarding unique preparations of DNA templates, their sequencing, registration, retrieval and evaluation of the nucleotide sequences with novel bioinformatics approaches [4]. A principal benefit of the new-generation sequencing is an opportunity get large databases of multiple defi ned oligonucleotide sequences within a short time period with low costs.
Out of all known HLA loci, the relatively important and most commonly used for transplantation of hematopoietic cells are HLA – A, B, C, DRB1 and DQB1 (Fig. 1). The American Society for Histocompatibility and Immunogenetics (ASHI) established a catalogue of common and well‐documented (CWD) HLA. It is very commonly used now around the world as a great tool for resolving typing ambiguities in tissue transplantation or for checking the universality of any HLA allele in the world [5]. There established catalogues (database). Th e total number of CWD alleles is similar in the EFI (N = 1048) and ASHI (N = 1031) catalogues [6] (http://igdawg.org/cwd.html).
The importance of only Exons 2 and 3 for the Class I and Exon 2 for Class II is very well-known and designated as coding proteins involved in antigen presentation in the major histocompatibility complex (MHC) receptor grove in-between the two helices accommodates peptides and interaction between an alloantibody IgG complex.
HLA alleles having nucleotide sequences that encode the same protein sequence for the peptide binding domains (exon 2 and 3 for HLA class I and exon 2 only for HLA class II alleles) designated by an upper case ‘P’ which follows the allele designation of the lowest numbered allele in the group. HLA alleles that have identical nucleotide sequences for the exons encoding the peptide binding domains (exon 2 and 3 for HLA class I and exon 2 only for HLA class II alleles) designated by an upper case ‘G’ which follows the allele designation of the lowest numbered allele in the group.
The first two digits describe the allele family, which oft en corresponds to the serological antigen carried by the allotype. The third and fourth digits assigned in the order in which the sequences have been determined. Alleles whose numbers diff er in the fi rst four digits must diff er by one or more nucleotide substitutions that change the amino-acid sequence of the encoded protein. Alleles that differ only by synonymous nucleotide substitutions within the coding sequence distinguished by the use of the fifth and sixth digits. Alleles that only differ by sequence polymorphisms in introns or in the 5’ and 3’ untranslated regions that fl ank the exons and introns distinguished by the use of the seventh and eight digits [7].
Figure 1. Current mapping of HLA loci on the chromosome 6 [Robinson J et al.] http://www.hla.alleles.org/alleles/index.html
No wonder that the general NGS approach adapted for HLA typing proved to be a breakthrough in molecular biology applications being quite promising to the transplantation clinics and bone marrow donor registries. However, to promote the NGS implementation, we need specialized typing strategies and digital program algorithms. The sequencing costs per single run sharply decreased with NGS approach, which may be accessible to the small size tissue typing laboratories in a sooner time [8].
However, despite higher resolution of NGS [9], it was necessary to conduct a comparative analysis of control samples with "rare" genotypes. It is also important to understand the cost-eff ectiveness of diff erent methods. Hence, the aim of this pilot study was to evaluate the comparative advantages of using NGS and the Sanger sequencing approach, to identify rare HLA alleles, and to estimate the costs for the both different methods.
Materials and methods
The potential donor's test samples were obtained from the Bone Marrow Donor Registry at the First I. P. Pavlov State Medical University of St. Petersburg, Russia, Raisa Gorbacheva Memorial Institute of Children's Hematology, Oncology, and Transplantation, and various hematology patients undergoing HLA SBT testing for planned allogeneic hematopoietic stem cell transplantation.
Genomic DNA was isolated from peripheral blood leukocytes using MagNA Pure System (Roche Life Science). The target DNA concentration was from 10 to 140 ng/μL. Quantity and quality estimation of the isolated DNA was performed with Quantus Fluorometer TM (Promega Corp., USA). The main steps of the NGS as performed with Illumina platform (MiSeq, USA) using NGSgo protocol were as follows:
1. HLA locus-specifi c amplifi cation: the complete sequences of HLA genes are amplifi ed with allele-specifi c primers in a single reaction for each locus using Long-Range DNA polymerase;
2. DNA quantifi cation by Quantus Fluorometer and pooling of amplicons according to the volumes calculated by the NGSgo Pooling Calculation Sheet (provided by GenDx, Netherlands);
3. Double-stranded DNA fragmentation by means of specific fragmentase optimized by its size for the specifi c HLA locus, end repair, 5’ phosphorylation of poly-A and poly-T ends and adapter ligation (Fig. 2);
4. DNA cleanup and size selection with 0.45x SPRI beads using 80% ethanol (Beckman Coulter, AMPure XP);
5. Indexing PCR products using a unique combination of i5 and i7 primers for each sample;
6. Plate-based DNA cleanup and size selection with 0.6x SPRI beads using 80% ethanol (Beckman Coulter, AMPure XP);
7. Plate-based library pooling, library quantifi cation performed using Qubit Fluorometer and loading to the NGS sequencer (MiSeq, Illumina, USA);
8. Next-generation sequencing by MiSeq and data analysis.
The libraries are sequenced on an Illumina NGS platform. The FastQ data can be analyzed with an HLA typing soft ware package to determine the HLA typing (for example, NGS engine). To assign the HLA alleles, the soft ware allows communicating with updated IMGT database (Fig. 3).
The NGS method allows performing sequencing of all exons in the A, B, and C HLA loci and three exons (from second to fourth) of DQB1 and DRB1 (Fig. 4) which, however, has its limitations. Th e allele imbalances can be observed in some
rare cases:
• NGSgo HLA-DRB1: allele imbalances for DRB1*01, DRB*04, and DRB1*14 alleles can occur in case of imbalanced amplifi cation.
• NGSgo HLA-DRB4: allele imbalances for DRB2 exon 2 and exon 3 can occur in case of imbalanced DRB4 amplifi cation. In the case of an HLA-DRB4 exon 3 amplicon dropout, limit the analysis to exon 2 only.
• NGSgo HLA-DRB3/4/5: allele imbalances for heterozygous DRB3/4/5 samples can occur in case of imbalanced amplicon pooling. Analysis of DRB3/4/5 has been optimized in NGSengine v2.1 (and higher), which applies a split-analysis of the individual DRB3/4/5 loci to improve HLA typing.
Th e main steps of Sanger sequencing when performed with Applied Biosystems Genetic Analyzer (USA) 3500xl genetic analyzer using PROTRANS HLA SBT Class I and Class II S4 (Hockenheim, Germany, http://www.protrans.info/nano.cms/en/products/MainCatID/9/). Single Allele, Allele- Group and Locus Specific Sequencing. Fourteen specific primer mixes pre-pipetted in 8 and 16 well strip, in order of sequencing the Exons 1, 2, 3 and 4 for Class I, Exon 2 for DRB1 and Exon 2, 3 for DQB1, according to the manufacturers’ recommendations.
Figure 2. Gene library preparation with NGSgo – LibX and NGSgo – IndX referred from https://www.gendx.com [10]
Figure 3. Data analysis software (NGSengine, https://www.gendx.com)
Figure 4. Target generation with NGSgo – AmpX [10]
Direct automated fl uorescent DNA sequencing was performed by a 24-channel automated capillary electrophoresis system, and fl uorescent detection of DNA fragments using an Applied Biosystems GA3500xl Genetic Analyzer. Capillary electrophoresis proceeded in the POP-7 polymer under denaturation conditions. Th e data on nucleotide sequences were retrieved at a stationary computer in the Data Collection program, then having been analyzed by Protrans SEQUENCE PILOT soft ware (Hockenheim, Germany).
DNA amplification kits for Sanger sequencing are designed to provide high-resolution identifi cation of alleles of the human HLA-A, -B, -C, -DRB1, -DQB1 genes.
Results
The aim of our pilot study was a comparison of two methods and an evaluation of their eff ectiveness. To achieve our purpose, we selected a group of 35 persons (see Materials and methods), and conducted analysis by Sanger and NGS method in parallel. Th e NGS method allowed detecting rare variants of alleles when performing data analysis with NGSengine soft ware (Fig. 5).
We have conducted two sets of experiments. Mean coverage in the fi rst experiment was 881x – (1010x, 897x, 768x, 807x, 923x, respectively for A-, B-, C-, DRB-, DQB- loci), and 992x in a second experiment (1194x, 856x, 698x, 1001x, 1346x, respectively for A-, B-, C-, DRB-, DQB- loci).
Mean percentage of aligned reads to the total read number was 96.5% in the fi rst set (DRB locus, 92.6%, other loci, >97.2%). In the second set, an appropriate percentage of aligned reads to the total read number was 95.0% (DRB locus, 91.6%, other loci, >95.5%) (Fig. 6). This metrics shows a high quality of the sequencing that was performed according to the manufacturer’s instructions.
To perform a more detailed analysis of each sample, the NGSengine soft ware contains the sections of «typing results» and «visualization», where the coverage for diff erent regions may be registered in more details, or a nucleotide position of interest should be found (Fig. 7).
Figure 5. A typical data evaluation table presented by NGSengine software (Genome Diagnostics, Netherlands)
It presents information for each locus (HLA-A, -B, -C, -DRB1, -DQB1) for single samples. Data on total read number and percentage of aligned reads for the given locus, mean read length, mean coverage, alleles identifi ed and presence of synonymous substitutions in coded [Ex] and it also displays non-coding [In] regions.
Figure 6. Statistics for samples (percentage aligned reads from total number of reads and number of reads mapped to the reference per strand) in NGSengine software
Figure 7. The results of the NGS sequencing all alleles for sample “3” and visualization of HLA-A locus for sample “3” in NGSengine software
It displays typing results for all HLA loci assayed. Th e cases of ambiguous results shown as Allele Ambiguities. In our series, no ambiguities were detectable for any locus. The figure visualization allows us to look at the visual segment (it shows exons in yellow). It indicates the sequencing coverage of the given locus below (marked gray). The vertical ticks seen at appropriates points of HLA loci in cases of synonymous nucleotide substitutions.
Table 1. Comparison of allele sequenced by NGS and Sanger’s method – 100% homology results (there are no differences in 2nd and 3rd exons sequences)
Factors contributing to the costs arising for the in-depth sequencing
The reagents for the entire HLA-sequencing process include those used for routine pre-analytic steps (e.g., DNA extraction, quality assessment, and initial low-resolution typing step). Additional expenditures are subject to some ambiguities, due to diff erent prices for reagents and equipment off ered by distinct manufacturers. Moreover, it should be addressed that all the commercial NGS platforms off er their closed-type systems, thus causing broad variations in prices for the entire NGS procedure per single DNA sample, strongly depending on the annual capacity of the given HLA typing laboratory.
However, even considering maintenance costs (about 10% equipment cost), enrolling third-party core facilities or shared equipment, the Sanger sequencing (220 K) proves to be twice more expensive than NGS (variable, but still less than Sanger technique), as shown elsewhere [11]. Hence, the sample preparation costs remain the same whereas the sequencing tends to decrease as discussed in [9]. Calculations of economic efficiency for HLA typing in Russia by Sanger technique versus NGS were among our major tasks. Therefore, we have performed a pricing for the sequencing kits at a company providing reagents to this purpose. Th e request was made twice (February 2017 and August 2018). The reagent price in Euros did not change suffi ciently. Of note, the sequencing kits by Sanger are produced for 25 or 100 tests, whereas NGS kits are off ered for 24 and 96 tests.
Clear benefit of Sanger approach is that a single locus may be sequenced in the sample, being, however, economically ineff ective when using NGS technology.
Hence, we have compared the panels for 100 tests covering fi ve main HLA loci, i.e., AlleleSEQR HLA-A PCR/Sequencing Mix, AlleleSEQR HLA-B PCR/Sequencing Mix, AlleleSEQR HLA-C Plus PCR/Sequencing Mix, AlleleSEQR HLA-DRB1 PCR/Sequencing Mix, AlleleSEQR HLA-DQB1 PCR/Sequencing Mix). Each set was purchased for 6250 Euros. Hence, the total cost of locus-specifi c reagents for 5 loci was 31250 Euros, thus providing 312.50 Euros per 1 human DNA sample (ca. 24,000 roubles as per October 2018). The prime costs should also include disposables for the core sequencing procedure. E.g., if performing 100 tests for 5 HLA loci, we run 2500 reactions with a 24-channel Applied Biosystems GA3500xl Genetic Analyzer ABI 3500. To start the process, the following general items are needed: 26 plates for the gene analyzer (MicroAmp 96 Well Reaction Plate); three universal polymers. For capillary electrophoresis, POP-7 for 960 samples, fi ve Formamide packs (25 mL each), containers with anode and cathode buff ers etc., at a total price of 4500 Euros. Hence, the prime costs of Sanger reagents, when sequencing 5 main loci at the full-load regimen and usage of a 100-test kit, makes about 35750 Euros (ca. 2681250 roubles), excluding costs for pipette tips, microtubes, gloves and other inexpensive disposables. Th at means ca. 27000 roubles per one human DNA sample.
When applying NGS approach, the number of samples taken into analysis is quite suffi cient, since even a high-throughput MiSeq machine may perform sequencing of up to 269 samples in parallel, using a standard 4.5-Gb cartridge.
To calculate costs of comparable NGS analysis, we have chosen a reagent set for sequencing of 96 samples which incuded the following items: NGSgo®-AmpX HLA-A, B, C, DRB1, DQB1, NGSgo®-LibrX Library Preparation (2 kits), NGSgo ®-IndX Adapter & Indices (4x24) RUO Illumina, Agencourt AMPure XP 5 mL Kit, GenDx LongRange polymerase (3 kits), MiSeq Reagent Kit v2. A total sum for typing 5 loci made ca. 14 800 Euros, thus comprising 155 Euros (>10000 Roubles) per sample.
However, in case of spared use of the reagents for sample preparation by two-fold decrease in reaction volume (as proven by our experience), the prime costs per a single test dropped to 90 Euros. Th e self-cost is here provided without accessory disposables.
Hence, the costs of sequencing reagents, even without their sparing, is suffi ciently cheaper when using NGS technologies. Moreover, the procedure takes 2-fold less time for its performance than the Sanger technique.
Conclusion
Comparison of allele sequenced by NGS and Sanger’s method yielded 100% homology results. Hence, our work is in accordance with previously published data [9], which demonstrate the advantage and effi ciency of NGS, as compared to Sanger sequencing.
NGS-based HLA analysis is performed with a 100% reliability, and well fi ts the tasks of HLA typing in unrelated donors, in concordance with EFI and ASHI policies. Th is work process well corresponds to the working schedules for medium- and high-capacity laboratories, thus being potentially attractive to the donor registries. Recently introduced next-generation sequencing techniques have a facilitating potential for the high-resolution genotyping via a decrease of general ambiguity of end results, like as due to more extended sequencing regions. In near future, the NGS approaches will be an eff ective and cost-eff ective technology when evaluating histocompatibility parameters and immunogenetic interactions.
Conflict of interest
The authors have declared no conflicting interests.
Funding
This research was funded by Russian Science Foundation grant №14-50-00069.
References
1. Robinson J, Halliwell JA, Hayhurst JH, Flicek P, Parham P, Marsh SGE. Th e IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Research. 2015; 43:D423-431.
2. Marsh SGE, Albert ED, Bodmer W, Bontrop RE, Dupont B, Erlich HA, Fernández-Viña M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW , Mach B, Maiers M, Mayr WR, Müller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J. Nomenclature for factors of the HLA system, 2010. Tissue Antigens. 2010; 75(4):291-455.
3. Marsh SGE. Nomenclature for factors of the HLA system, update July 2017. Human Immunol. 2017; 78(11-12):758- 761.
4. Holcomb CL, Höglund B, Anderson MW, Blake LA, Böhme I, Egholm M, Ferriola D, Gabriel C, Gelber SE, Goodridge D, Hawbecker S, Klein R, Ladner M, Lind C, Monos D, Pando MJ, Pröll J, Sayer DC, Schmitz-Agheguian G, Simen BB, Th iele B, Trachtenberg EA, Tyan DB, Wassmuth R, White S, Erlich HA.A multi-site study using high-resolution HLA genotyping by next generation sequencing. // Tissue Antigens. 2011;77(3):206-217. doi: 10.1111/j.1399-0039.2010.01606.x.
5. Mack SJ1, Cano P, Hollenbach JA, He J, Hurley CK, Middleton D, Moraes ME, Pereira SE, Kempenich JH, Reed EF, Setterholm M, Smith AG, Tilanus MG, Torres M, Varney MD, Voorter CE, Fischer GF, Fleischhauer K, Goodridge D, Klitz W, Little AM, Maiers M, Marsh SG, Müller CR, Noreen H, Rozemuller EH, Sanchez-Mazas A, Senitzer D, Trachtenberg E, Fernandez-Vina M. Common and well-documented HLA alleles: 2012 update to the CWD catalogue. Tissue Antigens. 2013 Apr;81(4):194-203. doi: 10.1111/tan.12093.
6. A. Sanchez‐Mazas, J. M. Nunes, D. Middleton, J. Sauter, S. Buhler, A. McCabe, J. Hofmann, D. M. Baier, A. H. Schmidt, G. Nicoloso, M. Andreani, Z. Grubic, J.‐M. Tiercy, K. Fleischhaue.r Common and well‐documented HLA alleles over all of Europe and within European sub‐regions: A catalogue from the European Federation for Immunogenetics. HLA Volume 89, Issue2.February 2017 Pages 104-113.
7. S. G. E. Marsh, E. D. Albert, W. F. Bodmer, R. E. Bontrop, B. Dupont, H. A. Erlich, M. Ferna´ndez-Vin˜ a, D. E. Geraghty, R. Holdsworth, C. K. Hurley, M. Lau, K. W. Lee, B. Mach, M. Maiers, W. R. Mayr, C. R. Mu¨ ller, P. Parham, E. W. Petersdorf, T. Sasazuki, J. L. Strominger, A. Svejgaard, P. I. Terasaki, J. M. Tiercy & J. Trowsdale. Nomenclature for factors of the HLA system, 2010 Tissue Antigens 75, 291-455.
8. Kuzmich EV, Alyanskiy AL, Tyapushkina SS, Nasredinova AA, Ivanova NE, Zubarovskaya LS, Afanasyev BV. Identifi cation of the new HLA-B*44:02:45, DQB1*02:85, DQB1*06:210, DRB1*01:01:30 alleles by monoallelic Sanger sequencing. Cell Th er Transplant. 2018. 7(1):62-66. 9. Serov YA, Barkhatov IM, Klimov AS, Berkos AS. Current methods and opportunities of next-generation sequencing (NGS) for HLA typing // Cell Th er Transplant. 2016; 5(4): 63-70. doi: 10.18620/ctt-1866-8836-2016-5-4-63-70.
10. https://www.gendx.com
11. Baxter-Lowe LA. Tailoring NGS for smaller volume labs. Proc. 42nd ASHI Annual Meeting. Abstract: Sept 28, 2016.
Introduction
The Major Histocompatibility Complex (MHC) is among the most polymorphic genetic systems in humans. Over last decade, extensive research in HLA (Human Leukocyte Antigens) has revealed hundreds of new HLA alleles through intensive application of immunogenetic sequencing methods, including monoallelic Sanger-sequencing method, or, more recently, next-generation sequencing. In September 2018, the database of the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System (IPD-IMGT/HLA Database) contained information on the nucleotide sequences of 20272 diff erent HLA alleles, of which 14800 were HLA class I and 5288 founded for the HLA class II alleles [1-3].
During last 20 years, the automated Sanger technique has become a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening required some novel technologies of multiplex DNA sequencing. It depicts these modern methods as the second-generation approaches (Next-Generation Sequencing, NGS). Th ese technological platforms based on diff erent strategies, regarding unique preparations of DNA templates, their sequencing, registration, retrieval and evaluation of the nucleotide sequences with novel bioinformatics approaches [4]. A principal benefit of the new-generation sequencing is an opportunity get large databases of multiple defi ned oligonucleotide sequences within a short time period with low costs.
Out of all known HLA loci, the relatively important and most commonly used for transplantation of hematopoietic cells are HLA – A, B, C, DRB1 and DQB1 (Fig. 1). The American Society for Histocompatibility and Immunogenetics (ASHI) established a catalogue of common and well‐documented (CWD) HLA. It is very commonly used now around the world as a great tool for resolving typing ambiguities in tissue transplantation or for checking the universality of any HLA allele in the world [5]. There established catalogues (database). Th e total number of CWD alleles is similar in the EFI (N = 1048) and ASHI (N = 1031) catalogues [6] (http://igdawg.org/cwd.html).
The importance of only Exons 2 and 3 for the Class I and Exon 2 for Class II is very well-known and designated as coding proteins involved in antigen presentation in the major histocompatibility complex (MHC) receptor grove in-between the two helices accommodates peptides and interaction between an alloantibody IgG complex.
HLA alleles having nucleotide sequences that encode the same protein sequence for the peptide binding domains (exon 2 and 3 for HLA class I and exon 2 only for HLA class II alleles) designated by an upper case ‘P’ which follows the allele designation of the lowest numbered allele in the group. HLA alleles that have identical nucleotide sequences for the exons encoding the peptide binding domains (exon 2 and 3 for HLA class I and exon 2 only for HLA class II alleles) designated by an upper case ‘G’ which follows the allele designation of the lowest numbered allele in the group.
The first two digits describe the allele family, which oft en corresponds to the serological antigen carried by the allotype. The third and fourth digits assigned in the order in which the sequences have been determined. Alleles whose numbers diff er in the fi rst four digits must diff er by one or more nucleotide substitutions that change the amino-acid sequence of the encoded protein. Alleles that differ only by synonymous nucleotide substitutions within the coding sequence distinguished by the use of the fifth and sixth digits. Alleles that only differ by sequence polymorphisms in introns or in the 5’ and 3’ untranslated regions that fl ank the exons and introns distinguished by the use of the seventh and eight digits [7].
Figure 1. Current mapping of HLA loci on the chromosome 6 [Robinson J et al.] http://www.hla.alleles.org/alleles/index.html
No wonder that the general NGS approach adapted for HLA typing proved to be a breakthrough in molecular biology applications being quite promising to the transplantation clinics and bone marrow donor registries. However, to promote the NGS implementation, we need specialized typing strategies and digital program algorithms. The sequencing costs per single run sharply decreased with NGS approach, which may be accessible to the small size tissue typing laboratories in a sooner time [8].
However, despite higher resolution of NGS [9], it was necessary to conduct a comparative analysis of control samples with "rare" genotypes. It is also important to understand the cost-eff ectiveness of diff erent methods. Hence, the aim of this pilot study was to evaluate the comparative advantages of using NGS and the Sanger sequencing approach, to identify rare HLA alleles, and to estimate the costs for the both different methods.
Materials and methods
The potential donor's test samples were obtained from the Bone Marrow Donor Registry at the First I. P. Pavlov State Medical University of St. Petersburg, Russia, Raisa Gorbacheva Memorial Institute of Children's Hematology, Oncology, and Transplantation, and various hematology patients undergoing HLA SBT testing for planned allogeneic hematopoietic stem cell transplantation.
Genomic DNA was isolated from peripheral blood leukocytes using MagNA Pure System (Roche Life Science). The target DNA concentration was from 10 to 140 ng/μL. Quantity and quality estimation of the isolated DNA was performed with Quantus Fluorometer TM (Promega Corp., USA). The main steps of the NGS as performed with Illumina platform (MiSeq, USA) using NGSgo protocol were as follows:
1. HLA locus-specifi c amplifi cation: the complete sequences of HLA genes are amplifi ed with allele-specifi c primers in a single reaction for each locus using Long-Range DNA polymerase;
2. DNA quantifi cation by Quantus Fluorometer and pooling of amplicons according to the volumes calculated by the NGSgo Pooling Calculation Sheet (provided by GenDx, Netherlands);
3. Double-stranded DNA fragmentation by means of specific fragmentase optimized by its size for the specifi c HLA locus, end repair, 5’ phosphorylation of poly-A and poly-T ends and adapter ligation (Fig. 2);
4. DNA cleanup and size selection with 0.45x SPRI beads using 80% ethanol (Beckman Coulter, AMPure XP);
5. Indexing PCR products using a unique combination of i5 and i7 primers for each sample;
6. Plate-based DNA cleanup and size selection with 0.6x SPRI beads using 80% ethanol (Beckman Coulter, AMPure XP);
7. Plate-based library pooling, library quantifi cation performed using Qubit Fluorometer and loading to the NGS sequencer (MiSeq, Illumina, USA);
8. Next-generation sequencing by MiSeq and data analysis.
The libraries are sequenced on an Illumina NGS platform. The FastQ data can be analyzed with an HLA typing soft ware package to determine the HLA typing (for example, NGS engine). To assign the HLA alleles, the soft ware allows communicating with updated IMGT database (Fig. 3).
The NGS method allows performing sequencing of all exons in the A, B, and C HLA loci and three exons (from second to fourth) of DQB1 and DRB1 (Fig. 4) which, however, has its limitations. Th e allele imbalances can be observed in some
rare cases:
• NGSgo HLA-DRB1: allele imbalances for DRB1*01, DRB*04, and DRB1*14 alleles can occur in case of imbalanced amplifi cation.
• NGSgo HLA-DRB4: allele imbalances for DRB2 exon 2 and exon 3 can occur in case of imbalanced DRB4 amplifi cation. In the case of an HLA-DRB4 exon 3 amplicon dropout, limit the analysis to exon 2 only.
• NGSgo HLA-DRB3/4/5: allele imbalances for heterozygous DRB3/4/5 samples can occur in case of imbalanced amplicon pooling. Analysis of DRB3/4/5 has been optimized in NGSengine v2.1 (and higher), which applies a split-analysis of the individual DRB3/4/5 loci to improve HLA typing.
Th e main steps of Sanger sequencing when performed with Applied Biosystems Genetic Analyzer (USA) 3500xl genetic analyzer using PROTRANS HLA SBT Class I and Class II S4 (Hockenheim, Germany, http://www.protrans.info/nano.cms/en/products/MainCatID/9/). Single Allele, Allele- Group and Locus Specific Sequencing. Fourteen specific primer mixes pre-pipetted in 8 and 16 well strip, in order of sequencing the Exons 1, 2, 3 and 4 for Class I, Exon 2 for DRB1 and Exon 2, 3 for DQB1, according to the manufacturers’ recommendations.
Figure 2. Gene library preparation with NGSgo – LibX and NGSgo – IndX referred from https://www.gendx.com [10]
Figure 3. Data analysis software (NGSengine, https://www.gendx.com)
Figure 4. Target generation with NGSgo – AmpX [10]
Direct automated fl uorescent DNA sequencing was performed by a 24-channel automated capillary electrophoresis system, and fl uorescent detection of DNA fragments using an Applied Biosystems GA3500xl Genetic Analyzer. Capillary electrophoresis proceeded in the POP-7 polymer under denaturation conditions. Th e data on nucleotide sequences were retrieved at a stationary computer in the Data Collection program, then having been analyzed by Protrans SEQUENCE PILOT soft ware (Hockenheim, Germany).
DNA amplification kits for Sanger sequencing are designed to provide high-resolution identifi cation of alleles of the human HLA-A, -B, -C, -DRB1, -DQB1 genes.
Results
The aim of our pilot study was a comparison of two methods and an evaluation of their eff ectiveness. To achieve our purpose, we selected a group of 35 persons (see Materials and methods), and conducted analysis by Sanger and NGS method in parallel. Th e NGS method allowed detecting rare variants of alleles when performing data analysis with NGSengine soft ware (Fig. 5).
We have conducted two sets of experiments. Mean coverage in the fi rst experiment was 881x – (1010x, 897x, 768x, 807x, 923x, respectively for A-, B-, C-, DRB-, DQB- loci), and 992x in a second experiment (1194x, 856x, 698x, 1001x, 1346x, respectively for A-, B-, C-, DRB-, DQB- loci).
Mean percentage of aligned reads to the total read number was 96.5% in the fi rst set (DRB locus, 92.6%, other loci, >97.2%). In the second set, an appropriate percentage of aligned reads to the total read number was 95.0% (DRB locus, 91.6%, other loci, >95.5%) (Fig. 6). This metrics shows a high quality of the sequencing that was performed according to the manufacturer’s instructions.
To perform a more detailed analysis of each sample, the NGSengine soft ware contains the sections of «typing results» and «visualization», where the coverage for diff erent regions may be registered in more details, or a nucleotide position of interest should be found (Fig. 7).
Figure 5. A typical data evaluation table presented by NGSengine software (Genome Diagnostics, Netherlands)
It presents information for each locus (HLA-A, -B, -C, -DRB1, -DQB1) for single samples. Data on total read number and percentage of aligned reads for the given locus, mean read length, mean coverage, alleles identifi ed and presence of synonymous substitutions in coded [Ex] and it also displays non-coding [In] regions.
Figure 6. Statistics for samples (percentage aligned reads from total number of reads and number of reads mapped to the reference per strand) in NGSengine software
Figure 7. The results of the NGS sequencing all alleles for sample “3” and visualization of HLA-A locus for sample “3” in NGSengine software
It displays typing results for all HLA loci assayed. Th e cases of ambiguous results shown as Allele Ambiguities. In our series, no ambiguities were detectable for any locus. The figure visualization allows us to look at the visual segment (it shows exons in yellow). It indicates the sequencing coverage of the given locus below (marked gray). The vertical ticks seen at appropriates points of HLA loci in cases of synonymous nucleotide substitutions.
Table 1. Comparison of allele sequenced by NGS and Sanger’s method – 100% homology results (there are no differences in 2nd and 3rd exons sequences)
Factors contributing to the costs arising for the in-depth sequencing
The reagents for the entire HLA-sequencing process include those used for routine pre-analytic steps (e.g., DNA extraction, quality assessment, and initial low-resolution typing step). Additional expenditures are subject to some ambiguities, due to diff erent prices for reagents and equipment off ered by distinct manufacturers. Moreover, it should be addressed that all the commercial NGS platforms off er their closed-type systems, thus causing broad variations in prices for the entire NGS procedure per single DNA sample, strongly depending on the annual capacity of the given HLA typing laboratory.
However, even considering maintenance costs (about 10% equipment cost), enrolling third-party core facilities or shared equipment, the Sanger sequencing (220 K) proves to be twice more expensive than NGS (variable, but still less than Sanger technique), as shown elsewhere [11]. Hence, the sample preparation costs remain the same whereas the sequencing tends to decrease as discussed in [9]. Calculations of economic efficiency for HLA typing in Russia by Sanger technique versus NGS were among our major tasks. Therefore, we have performed a pricing for the sequencing kits at a company providing reagents to this purpose. Th e request was made twice (February 2017 and August 2018). The reagent price in Euros did not change suffi ciently. Of note, the sequencing kits by Sanger are produced for 25 or 100 tests, whereas NGS kits are off ered for 24 and 96 tests.
Clear benefit of Sanger approach is that a single locus may be sequenced in the sample, being, however, economically ineff ective when using NGS technology.
Hence, we have compared the panels for 100 tests covering fi ve main HLA loci, i.e., AlleleSEQR HLA-A PCR/Sequencing Mix, AlleleSEQR HLA-B PCR/Sequencing Mix, AlleleSEQR HLA-C Plus PCR/Sequencing Mix, AlleleSEQR HLA-DRB1 PCR/Sequencing Mix, AlleleSEQR HLA-DQB1 PCR/Sequencing Mix). Each set was purchased for 6250 Euros. Hence, the total cost of locus-specifi c reagents for 5 loci was 31250 Euros, thus providing 312.50 Euros per 1 human DNA sample (ca. 24,000 roubles as per October 2018). The prime costs should also include disposables for the core sequencing procedure. E.g., if performing 100 tests for 5 HLA loci, we run 2500 reactions with a 24-channel Applied Biosystems GA3500xl Genetic Analyzer ABI 3500. To start the process, the following general items are needed: 26 plates for the gene analyzer (MicroAmp 96 Well Reaction Plate); three universal polymers. For capillary electrophoresis, POP-7 for 960 samples, fi ve Formamide packs (25 mL each), containers with anode and cathode buff ers etc., at a total price of 4500 Euros. Hence, the prime costs of Sanger reagents, when sequencing 5 main loci at the full-load regimen and usage of a 100-test kit, makes about 35750 Euros (ca. 2681250 roubles), excluding costs for pipette tips, microtubes, gloves and other inexpensive disposables. Th at means ca. 27000 roubles per one human DNA sample.
When applying NGS approach, the number of samples taken into analysis is quite suffi cient, since even a high-throughput MiSeq machine may perform sequencing of up to 269 samples in parallel, using a standard 4.5-Gb cartridge.
To calculate costs of comparable NGS analysis, we have chosen a reagent set for sequencing of 96 samples which incuded the following items: NGSgo®-AmpX HLA-A, B, C, DRB1, DQB1, NGSgo®-LibrX Library Preparation (2 kits), NGSgo ®-IndX Adapter & Indices (4x24) RUO Illumina, Agencourt AMPure XP 5 mL Kit, GenDx LongRange polymerase (3 kits), MiSeq Reagent Kit v2. A total sum for typing 5 loci made ca. 14 800 Euros, thus comprising 155 Euros (>10000 Roubles) per sample.
However, in case of spared use of the reagents for sample preparation by two-fold decrease in reaction volume (as proven by our experience), the prime costs per a single test dropped to 90 Euros. Th e self-cost is here provided without accessory disposables.
Hence, the costs of sequencing reagents, even without their sparing, is suffi ciently cheaper when using NGS technologies. Moreover, the procedure takes 2-fold less time for its performance than the Sanger technique.
Conclusion
Comparison of allele sequenced by NGS and Sanger’s method yielded 100% homology results. Hence, our work is in accordance with previously published data [9], which demonstrate the advantage and effi ciency of NGS, as compared to Sanger sequencing.
NGS-based HLA analysis is performed with a 100% reliability, and well fi ts the tasks of HLA typing in unrelated donors, in concordance with EFI and ASHI policies. Th is work process well corresponds to the working schedules for medium- and high-capacity laboratories, thus being potentially attractive to the donor registries. Recently introduced next-generation sequencing techniques have a facilitating potential for the high-resolution genotyping via a decrease of general ambiguity of end results, like as due to more extended sequencing regions. In near future, the NGS approaches will be an eff ective and cost-eff ective technology when evaluating histocompatibility parameters and immunogenetic interactions.
Conflict of interest
The authors have declared no conflicting interests.
Funding
This research was funded by Russian Science Foundation grant №14-50-00069.
References
1. Robinson J, Halliwell JA, Hayhurst JH, Flicek P, Parham P, Marsh SGE. Th e IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Research. 2015; 43:D423-431.
2. Marsh SGE, Albert ED, Bodmer W, Bontrop RE, Dupont B, Erlich HA, Fernández-Viña M, Geraghty DE, Holdsworth R, Hurley CK, Lau M, Lee KW , Mach B, Maiers M, Mayr WR, Müller CR, Parham P, Petersdorf EW, Sasazuki T, Strominger JL, Svejgaard A, Terasaki PI, Tiercy JM, Trowsdale J. Nomenclature for factors of the HLA system, 2010. Tissue Antigens. 2010; 75(4):291-455.
3. Marsh SGE. Nomenclature for factors of the HLA system, update July 2017. Human Immunol. 2017; 78(11-12):758- 761.
4. Holcomb CL, Höglund B, Anderson MW, Blake LA, Böhme I, Egholm M, Ferriola D, Gabriel C, Gelber SE, Goodridge D, Hawbecker S, Klein R, Ladner M, Lind C, Monos D, Pando MJ, Pröll J, Sayer DC, Schmitz-Agheguian G, Simen BB, Th iele B, Trachtenberg EA, Tyan DB, Wassmuth R, White S, Erlich HA.A multi-site study using high-resolution HLA genotyping by next generation sequencing. // Tissue Antigens. 2011;77(3):206-217. doi: 10.1111/j.1399-0039.2010.01606.x.
5. Mack SJ1, Cano P, Hollenbach JA, He J, Hurley CK, Middleton D, Moraes ME, Pereira SE, Kempenich JH, Reed EF, Setterholm M, Smith AG, Tilanus MG, Torres M, Varney MD, Voorter CE, Fischer GF, Fleischhauer K, Goodridge D, Klitz W, Little AM, Maiers M, Marsh SG, Müller CR, Noreen H, Rozemuller EH, Sanchez-Mazas A, Senitzer D, Trachtenberg E, Fernandez-Vina M. Common and well-documented HLA alleles: 2012 update to the CWD catalogue. Tissue Antigens. 2013 Apr;81(4):194-203. doi: 10.1111/tan.12093.
6. A. Sanchez‐Mazas, J. M. Nunes, D. Middleton, J. Sauter, S. Buhler, A. McCabe, J. Hofmann, D. M. Baier, A. H. Schmidt, G. Nicoloso, M. Andreani, Z. Grubic, J.‐M. Tiercy, K. Fleischhaue.r Common and well‐documented HLA alleles over all of Europe and within European sub‐regions: A catalogue from the European Federation for Immunogenetics. HLA Volume 89, Issue2.February 2017 Pages 104-113.
7. S. G. E. Marsh, E. D. Albert, W. F. Bodmer, R. E. Bontrop, B. Dupont, H. A. Erlich, M. Ferna´ndez-Vin˜ a, D. E. Geraghty, R. Holdsworth, C. K. Hurley, M. Lau, K. W. Lee, B. Mach, M. Maiers, W. R. Mayr, C. R. Mu¨ ller, P. Parham, E. W. Petersdorf, T. Sasazuki, J. L. Strominger, A. Svejgaard, P. I. Terasaki, J. M. Tiercy & J. Trowsdale. Nomenclature for factors of the HLA system, 2010 Tissue Antigens 75, 291-455.
8. Kuzmich EV, Alyanskiy AL, Tyapushkina SS, Nasredinova AA, Ivanova NE, Zubarovskaya LS, Afanasyev BV. Identifi cation of the new HLA-B*44:02:45, DQB1*02:85, DQB1*06:210, DRB1*01:01:30 alleles by monoallelic Sanger sequencing. Cell Th er Transplant. 2018. 7(1):62-66. 9. Serov YA, Barkhatov IM, Klimov AS, Berkos AS. Current methods and opportunities of next-generation sequencing (NGS) for HLA typing // Cell Th er Transplant. 2016; 5(4): 63-70. doi: 10.18620/ctt-1866-8836-2016-5-4-63-70.
10. https://www.gendx.com
11. Baxter-Lowe LA. Tailoring NGS for smaller volume labs. Proc. 42nd ASHI Annual Meeting. Abstract: Sept 28, 2016.
2 Институт трансляционной биомедицины, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
3 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский
государственный медицинский университет, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20916" ["VALUE"]=> array(2) { ["TEXT"]=> string(3069) "<p> База данных Всемирной организации здравоохранения (ВОЗ) Комитета по номенклатуре факторов <span style="text-align: justify;">системы HLA (база данных IPD-IMGT/HLA) на сен</span><span style="text-align: justify;">тябрь 2018 г. содержала информацию о нуклеотид</span><span style="text-align: justify;">ных последовательностях 20272 различных аллелей </span><span style="text-align: justify;">HLA, из которых 14800 были аллелями HLA класса I, </span><span style="text-align: justify;">а 5288 – класса II.</span> </p> <p style="text-align: justify;"> На протяжении последних 20 лет при секвенировании генома человека, животных, бактерий и вирусов преобладает автоматизированная технология Сэнгера. Однако необходимость более быстрого скрининга генома стимулировало развитие новых технологий мультиплексного секвенирования ДНК. Эти современные методы обозначаются как подходы следующего поколения (Next-Generation Sequencing, NGS). </p> <p style="text-align: justify;"> Целью нашего исследования было сравнение двух этих методов и оценка их эффективности. Чтобы достичь этой цели, мы выбрали группу из 35 образцов ДНК, в основном – потенциальных доноров гемопоэтических клеток, и провели сравнительный анализ по Сэнгеру и методом NGS. Метод NGS позволяет выявлять редкие или новые варианты аллелей. Этот подход подтвержден в качестве более чувствительного и более экономичного, особенно в больших лабораториях по HLA-типированию. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Главный комплекс гистосовместимости, новые аллели HLA, технологические решения, секвенирование следующего поколения, NGS, секвенирование по Сэнгеру, трансплантация гемопоэтических клеток, типирование по сиквенсам ДНК. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2859) "
База данных Всемирной организации здравоохранения (ВОЗ) Комитета по номенклатуре факторов системы HLA (база данных IPD-IMGT/HLA) на сентябрь 2018 г. содержала информацию о нуклеотидных последовательностях 20272 различных аллелей HLA, из которых 14800 были аллелями HLA класса I, а 5288 – класса II.
На протяжении последних 20 лет при секвенировании генома человека, животных, бактерий и вирусов преобладает автоматизированная технология Сэнгера. Однако необходимость более быстрого скрининга генома стимулировало развитие новых технологий мультиплексного секвенирования ДНК. Эти современные методы обозначаются как подходы следующего поколения (Next-Generation Sequencing, NGS).
Целью нашего исследования было сравнение двух этих методов и оценка их эффективности. Чтобы достичь этой цели, мы выбрали группу из 35 образцов ДНК, в основном – потенциальных доноров гемопоэтических клеток, и провели сравнительный анализ по Сэнгеру и методом NGS. Метод NGS позволяет выявлять редкие или новые варианты аллелей. Этот подход подтвержден в качестве более чувствительного и более экономичного, особенно в больших лабораториях по HLA-типированию.
Ключевые слова
Главный комплекс гистосовместимости, новые аллели HLA, технологические решения, секвенирование следующего поколения, NGS, секвенирование по Сэнгеру, трансплантация гемопоэтических клеток, типирование по сиквенсам ДНК.
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Glotov <sup>1</sup>,<sup>2</sup>, Olga V. Romanova <sup>1</sup>,<sup>2</sup>, Yuri A. Eismont <sup>1</sup>, Andrey M. Sarana <sup>1</sup>,<sup>2</sup>, Sergey G. Scherbak <sup>1</sup>,<sup>2</sup>, Elena V. Kuzmich <sup>3</sup>, Alexander L. Alyanskiy <sup>3</sup>, Natalya E. Ivanova <sup>3</sup>, Vera V. Teplyashina <sup>3</sup>, Yury A. Serov <sup>3</sup>, Ludmila S. Zubarovskaya <sup>3</sup>, Boris V. Afanasyev <sup>3</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(442) "Oleg S. Glotov 1,2, Olga V. Romanova 1,2, Yuri A. Eismont 1, Andrey M. Sarana 1,2, Sergey G. Scherbak 1,2, Elena V. Kuzmich 3, Alexander L. Alyanskiy 3, Natalya E. Ivanova 3, Vera V. Teplyashina 3, Yury A. Serov 3, Ludmila S. Zubarovskaya 3, Boris V. Afanasyev 3" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20919" ["VALUE"]=> array(2) { ["TEXT"]=> string(444) "<sup>1</sup> City Hospital №40, Sestroretsk, St. Petersburg, Russia<br> <sup>2</sup> Institute of Translation Biomedicine, St. Petersburg State University, St. Petersburg, Russia<br> <sup>3</sup> Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(390) "1 City Hospital №40, Sestroretsk, St. Petersburg, Russia
2 Institute of Translation Biomedicine, St. Petersburg State University, St. Petersburg, Russia
3 Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
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The database of the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System (IPD-IMGT/HLA Database) contained information on the nucleotide sequences of 20272 diff erent HLA alleles in September 2018, of which 14800 were HLA class I and 5288 were found for the HLA class II alleles. Over the last 20 years, the automated Sanger technique is a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening stimulated novel technologies of multiplex DNA sequencing. These modern methods are depicted as the second-generation approaches (Next-Generation Sequencing, NGS). The aim of our research was a comparison of two methods and their effi ciency evaluation. To achieve our purpose, we selected a group of 35 DNA samples, mainly from potential hematopoietic cells donors, and conducted a comparative analysis by Sanger and NGS method. NGS method allowed detecting rare or novel variants of alleles. This approach is confirmed to be more sensitive and more cost-eff ective, especially in large HLA-typing laboratories.
Keywords
Major histocompatibility complex, novel HLA alleles, technological solutions, next-generation sequencing, NGS, Sanger sequencing, hematopoietic cells transplantation, Sequence-Based Typing (SBT).
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Glotov <sup>1</sup>,<sup>2</sup>, Olga V. Romanova <sup>1</sup>,<sup>2</sup>, Yuri A. Eismont <sup>1</sup>, Andrey M. Sarana <sup>1</sup>,<sup>2</sup>, Sergey G. Scherbak <sup>1</sup>,<sup>2</sup>, Elena V. Kuzmich <sup>3</sup>, Alexander L. Alyanskiy <sup>3</sup>, Natalya E. Ivanova <sup>3</sup>, Vera V. Teplyashina <sup>3</sup>, Yury A. Serov <sup>3</sup>, Ludmila S. Zubarovskaya <sup>3</sup>, Boris V. Afanasyev <sup>3</sup><br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(442) "Oleg S. Glotov 1,2, Olga V. Romanova 1,2, Yuri A. Eismont 1, Andrey M. Sarana 1,2, Sergey G. Scherbak 1,2, Elena V. Kuzmich 3, Alexander L. Alyanskiy 3, Natalya E. Ivanova 3, Vera V. Teplyashina 3, Yury A. Serov 3, Ludmila S. Zubarovskaya 3, Boris V. 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" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20920" ["VALUE"]=> array(2) { ["TEXT"]=> string(1523) "<p style="text-align: justify;"> The database of the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System (IPD-IMGT/HLA Database) contained information on the nucleotide sequences of 20272 diff erent HLA alleles in September 2018, of which 14800 were HLA class I and 5288 were found for the HLA class II alleles. Over the last 20 years, the automated Sanger technique is a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening stimulated novel technologies of multiplex DNA sequencing. These modern methods are depicted as the second-generation approaches (Next-Generation Sequencing, NGS). The aim of our research was a comparison of two methods and their effi ciency evaluation. To achieve our purpose, we selected a group of 35 DNA samples, mainly from potential hematopoietic cells donors, and conducted a comparative analysis by Sanger and NGS method. NGS method allowed detecting rare or novel variants of alleles. This approach is confirmed to be more sensitive and more cost-eff ective, especially in large HLA-typing laboratories. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Major histocompatibility complex, novel HLA alleles, technological solutions, next-generation sequencing, NGS, Sanger sequencing, hematopoietic cells transplantation, Sequence-Based Typing (SBT). </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1457) "
The database of the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System (IPD-IMGT/HLA Database) contained information on the nucleotide sequences of 20272 diff erent HLA alleles in September 2018, of which 14800 were HLA class I and 5288 were found for the HLA class II alleles. Over the last 20 years, the automated Sanger technique is a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening stimulated novel technologies of multiplex DNA sequencing. These modern methods are depicted as the second-generation approaches (Next-Generation Sequencing, NGS). The aim of our research was a comparison of two methods and their effi ciency evaluation. To achieve our purpose, we selected a group of 35 DNA samples, mainly from potential hematopoietic cells donors, and conducted a comparative analysis by Sanger and NGS method. NGS method allowed detecting rare or novel variants of alleles. This approach is confirmed to be more sensitive and more cost-eff ective, especially in large HLA-typing laboratories.
Keywords
Major histocompatibility complex, novel HLA alleles, technological solutions, next-generation sequencing, NGS, Sanger sequencing, hematopoietic cells transplantation, Sequence-Based Typing (SBT).
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1457) "The database of the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System (IPD-IMGT/HLA Database) contained information on the nucleotide sequences of 20272 diff erent HLA alleles in September 2018, of which 14800 were HLA class I and 5288 were found for the HLA class II alleles. Over the last 20 years, the automated Sanger technique is a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening stimulated novel technologies of multiplex DNA sequencing. These modern methods are depicted as the second-generation approaches (Next-Generation Sequencing, NGS). The aim of our research was a comparison of two methods and their effi ciency evaluation. To achieve our purpose, we selected a group of 35 DNA samples, mainly from potential hematopoietic cells donors, and conducted a comparative analysis by Sanger and NGS method. NGS method allowed detecting rare or novel variants of alleles. This approach is confirmed to be more sensitive and more cost-eff ective, especially in large HLA-typing laboratories.
Keywords
Major histocompatibility complex, novel HLA alleles, technological solutions, next-generation sequencing, NGS, Sanger sequencing, hematopoietic cells transplantation, Sequence-Based Typing (SBT).
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3 Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
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2 Institute of Translation Biomedicine, St. Petersburg State University, St. Petersburg, Russia
3 Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
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Афанасьев 3" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20916" ["VALUE"]=> array(2) { ["TEXT"]=> string(3069) "<p> База данных Всемирной организации здравоохранения (ВОЗ) Комитета по номенклатуре факторов <span style="text-align: justify;">системы HLA (база данных IPD-IMGT/HLA) на сен</span><span style="text-align: justify;">тябрь 2018 г. содержала информацию о нуклеотид</span><span style="text-align: justify;">ных последовательностях 20272 различных аллелей </span><span style="text-align: justify;">HLA, из которых 14800 были аллелями HLA класса I, </span><span style="text-align: justify;">а 5288 – класса II.</span> </p> <p style="text-align: justify;"> На протяжении последних 20 лет при секвенировании генома человека, животных, бактерий и вирусов преобладает автоматизированная технология Сэнгера. Однако необходимость более быстрого скрининга генома стимулировало развитие новых технологий мультиплексного секвенирования ДНК. Эти современные методы обозначаются как подходы следующего поколения (Next-Generation Sequencing, NGS). </p> <p style="text-align: justify;"> Целью нашего исследования было сравнение двух этих методов и оценка их эффективности. Чтобы достичь этой цели, мы выбрали группу из 35 образцов ДНК, в основном – потенциальных доноров гемопоэтических клеток, и провели сравнительный анализ по Сэнгеру и методом NGS. Метод NGS позволяет выявлять редкие или новые варианты аллелей. Этот подход подтвержден в качестве более чувствительного и более экономичного, особенно в больших лабораториях по HLA-типированию. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Главный комплекс гистосовместимости, новые аллели HLA, технологические решения, секвенирование следующего поколения, NGS, секвенирование по Сэнгеру, трансплантация гемопоэтических клеток, типирование по сиквенсам ДНК. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2859) "
База данных Всемирной организации здравоохранения (ВОЗ) Комитета по номенклатуре факторов системы HLA (база данных IPD-IMGT/HLA) на сентябрь 2018 г. содержала информацию о нуклеотидных последовательностях 20272 различных аллелей HLA, из которых 14800 были аллелями HLA класса I, а 5288 – класса II.
На протяжении последних 20 лет при секвенировании генома человека, животных, бактерий и вирусов преобладает автоматизированная технология Сэнгера. Однако необходимость более быстрого скрининга генома стимулировало развитие новых технологий мультиплексного секвенирования ДНК. Эти современные методы обозначаются как подходы следующего поколения (Next-Generation Sequencing, NGS).
Целью нашего исследования было сравнение двух этих методов и оценка их эффективности. Чтобы достичь этой цели, мы выбрали группу из 35 образцов ДНК, в основном – потенциальных доноров гемопоэтических клеток, и провели сравнительный анализ по Сэнгеру и методом NGS. Метод NGS позволяет выявлять редкие или новые варианты аллелей. Этот подход подтвержден в качестве более чувствительного и более экономичного, особенно в больших лабораториях по HLA-типированию.
Ключевые слова
Главный комплекс гистосовместимости, новые аллели HLA, технологические решения, секвенирование следующего поколения, NGS, секвенирование по Сэнгеру, трансплантация гемопоэтических клеток, типирование по сиквенсам ДНК.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2859) "База данных Всемирной организации здравоохранения (ВОЗ) Комитета по номенклатуре факторов системы HLA (база данных IPD-IMGT/HLA) на сентябрь 2018 г. содержала информацию о нуклеотидных последовательностях 20272 различных аллелей HLA, из которых 14800 были аллелями HLA класса I, а 5288 – класса II.
На протяжении последних 20 лет при секвенировании генома человека, животных, бактерий и вирусов преобладает автоматизированная технология Сэнгера. Однако необходимость более быстрого скрининга генома стимулировало развитие новых технологий мультиплексного секвенирования ДНК. Эти современные методы обозначаются как подходы следующего поколения (Next-Generation Sequencing, NGS).
Целью нашего исследования было сравнение двух этих методов и оценка их эффективности. Чтобы достичь этой цели, мы выбрали группу из 35 образцов ДНК, в основном – потенциальных доноров гемопоэтических клеток, и провели сравнительный анализ по Сэнгеру и методом NGS. Метод NGS позволяет выявлять редкие или новые варианты аллелей. Этот подход подтвержден в качестве более чувствительного и более экономичного, особенно в больших лабораториях по HLA-типированию.
Ключевые слова
Главный комплекс гистосовместимости, новые аллели HLA, технологические решения, секвенирование следующего поколения, NGS, секвенирование по Сэнгеру, трансплантация гемопоэтических клеток, типирование по сиквенсам ДНК.
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3 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский
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Introduction
Treatment of infl ammatory periodontal diseases (IPD) still represents a lot of issues. Th e global IPD prevalence among adults, according to the WHO data, is up to 90-95% without any trends for decrease [1, 2]. Medical treatment of IPD patients should be performed in combined, purposeful and personalized manner. Both local and general treatment should be applied, using effi cient methods of conservative, surgical and prosthetic treatment [1, 2].
Moreover, some novel treatments are recently introduced, based on cellular engineering, aiming for partial or total replacement of the damaged tissues. Such techniques presume modeling and construction of biocompatible (scaff old-type) carrier containing medical drugs. Th e main requirements for the modern matrix materials are as follows: complete biological compatibility, sustained viability of the cells seeded in the matrix, ability for biodegradation and replacement by normal tissues, changes in structure and properties fi tting the environmental eff ects [3].
Th e tissue engineering techniques are widely used in the IPD surgical treatment, especially when using the so-called directed tissue regeneration (DTR), i.e., a surgical approach which mechanically prevents epithelial migration to the apical side, thus promoting periodontal recovery without usage of natural and synthetic materials for the bone plastics. Th e method is aimed for creation of physical barrier between the graft and treated dental root surface resulting into preferential migration of slowly regenerating periodontal and bone cells to the aff ected site [4].
Both biodegradable and non- biodegradable membranes are now used at the present time when performing the directed tissue regeneration (DTR). Th ey may be classifi ed by their origin and composition, as shown in Table 1. Polytetrafl uorethylene (PTFE) is oft en used for manufacturing the non-biodegradable synthetic membranes. Th e PFTE non-biodegradable membranes are considered a “golden standard” for the DTR methodology. Th e results obtained with other membranes are usually compared to this PFTE material which has several advantages: essential mechanical resistance, no bone fi ller is required, and suffi cient barrier properties are present. PFTE drawbacks include a need for repeated surgical intervention 4 to 6 weeks for its extraction, complete closure of the membrane when sealing the flap with reliable fi xation; a need for regular weekly or biweekly inspections [4, 5, 6].
Table 1. Listing of the main membrane types [5]
Natural membranes represent structures consisting of animal collagen (xenogeneic), or allogeneic membranes which contain allogeneic collagen supplied by lyophilized demineralized bone, or membranes consisting of xenogeneic collagen and reduced amounts of mineral matrix obtained aft er partial electrolytic plate demineralization. All these membranes are based on, mainly, type I collagen. Th eir biodegradation continues for 5 to 6 months, barrier functions retain for 4 months, with good adhesion properties and only rare complications upon their exposure. Such membrane plate is elastic, thus requiring bone plastic materials in order to retain the space. Given long resorption rates, this material should be chosen for defects with presumed slow regeneration. Synthetic membranes are produced as polymeric and gel-like structures. Th e gel membranes are subject to biodegradation within 9 to 12 months, with their barrier properties kept for 6 months. However, it is more diffi cult to work with these materials which are rather hard upon polymerization. This type of membranes is now less common applied in dentistry due to problems when handling them. Th e procedure needs much time in cases of indirect usage, when the membrane is shaped beyond surgical area, followed by introduction to the damaged area [4, 5, 6].
There are no clear benefi ts revealed for either biodegradable, or non-biodegradable membranes. Th erefore, some authors, when comparing parameters of diff erent materials for the membrane fabrication, have considered chitosan to be the most promising substance which exhibits chondro- and osteoconductive properties, high degree of biocompatibility and complete biodegradation of the polymer, as well as expressed antibacterial activity and homeostatic effi ciency [7, 8, 9].
Chitosan is a desialylated form of chitin polymer which is widely spread in living nature. It seems to be a promising raw material for matrices and biomimetics of bone and cartilageous tissues. At the present time, chitosan is increasingly used in dentistry since it meets the requirements for potential matrix base [8, 9, 10].
Chitosan applied as the matrix scaff old allows prevention of immune-related synthesis, thus increasing biocompatibility of the composite matrices. Chemical properties of chitosan provide diff erent modifi cations of its polymer structure, incorporation of various biologically active compounds (both organic and inorganic substances), thus being an important factor. [11, 12, 13, 14]. One should also note that electrostatic and hydrophobic interaction of chitosan with some modifying agents may even enhance its biological activity. Th e aim of this study was to investigate the eff ectiveness of using chitosan membranes for the treatment of infl ammatory periodontal diseases.
Materials and methods
At the present time, we perform a joint study by the Department of Preventive Stomatology, Department of Biotechnology at the R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology (1st St. Petersburg State I. Pavlov Medical University), and the Research Institute of Macromolecular Compounds (Russian Academy of Sciences), concerning development and implementation of an original approach to surgical treatment of infl ammatory periodontal diseases using a novel chitosan-based matrix (Fig. 1), as described elsewhere [6].
Figure 1. A micrograph of chitosan-based matrix was obtained employing Carl Zeiss Supra 55 VP microscopy, magnification 500X. Micrographs (HC. 500X) of chitosan A and B-based membranes were obtained with a Carl Zeiss Supra 55 VP scanning electron microscope
Micrographs A and B are made by P. Popryadukhin
To produce porous membranes, we purchased Chitosan from Fluka Chemie, BioChemika line (molecular mass, 255 kD, deacetylation degree, 80%; ash content, 0.5%). Porous 3-D matrices were obtained by lyophilization of chitosan solution by means of Heto-Holten PowerDry PL9000 -50 device. Before drying, chitosan was dissolved in 2% aqueous solution of acetic acid, at 4 wt%. Th e solvent sublimation in the lyophilizer proceeded for 48 hours. As seen in Fig. 1, pores in the chitosan matrices look like channels, with the diameter of 100 to 150 nm [4].
Th e in vivo experiments with porous chitosan membranes were carried out in rabbits (n=10). Experimental studies were scheduled and performed according to the Guidelines from the Order No.1179 of 10.10.1983, and No.267 of 19.06.2003 issued by the Russian Ministry of Healtcare, European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientifi c Purposes (Strasbourg, 1986), as well as with World Medical Association Declaration of Helsinki (1996).
Table 2 presents the design of experimental study. All surgical interventions proceeded under identical conditions. Th e surgical manipulations were performed under general anesthesia, i.e., Zoletil100, 0.1 mL, and Rometerum (20 mg/mL), 0.0125 mL intravenously.
Two diff erent surgical procedures were performed in rabbits under sterile conditions, aiming for studies of chitosan matrix biocompatibility with adjacent tissues. The surgery was performed in extraoral mode. The operation field was prepared in the right maxillar area. A 5-cm incision was made in maxillar projection, while dissecting the tissue in sharp or blunt way. Aft er accessing the maxilla, an artifi cial bone defect was inflicted, then overlaid by the tested material. Blood coagulation was controlled, and the wound was closed with suture materials layer-by-layer and treated by a tincture of iodine.
Eight rabbits were subjected to the skin and soft tissue incision at the anterior lateral chest surface followed by a rib exposure and infl iction of a bone defect (10 to 12 mm long). The resulting cavity was filled with a biodegradable porous chitosan-based matrix.
Systemic antibacterial therapy was performed during early postsurgical period (3 days) using Gentamycin (single injections of 2.0 mL daily for 3 days). After surgical procedures, the rabbits were placed to individual cages. Th e animals had free access to water and standard diet, being regularly observed. The animals were kept out of experiment, according to the schedule (1 to 6 months aft er the surgical intervention), followed by histological studies of gums and ribs, i.e., the areas of artifi cial bone defects with introduced synthetic materials.
Results
Three months aft er surgery, histological assessment of gingival tissues did not reveal any pathological changes of oral mucosa; the multilayer fl at non-squamous epithelium and underlying connective tissue did not show any signs of inflammatory response (Fig. 2).
Table 2. Experimental study design
Morphological examination of artifi cially damaged ribs with implanted material has revealed multi-component changes of bone tissue and porous matrix. Morphological analysis of the matrix/bone border area has shown a lot of osteoclasts at the site of bone defect 30 days aft er surgery (Fig. 3)
Fibrous connective tissue penetrated by blood vessels is developing between the bone structures and porous template. The matrix is repopulated by fi broblasts and macrophages from local blood vessels and connective tissue, as well as from the developing periosteal layer. The entire porous matrix is occupied by connective tissue cells by 30 days of experiment. The intra-matrix fi broblasts are actively producing intercellular components of connective tissue. Due to biodegradation of the matrix and phagocytic activity of macrophages, the microcavities are formed which become larger than initial pores. Hence, the matrix pores and newly developing cavities become surrounded by connective tissue structures containing big amounts of collagen fi bers and cell composition typical to the fi brous connective tissue. Moreover, the implant areas adjacent to newly formed periosteum, are more rich in connective tissue, as compared to the more centrally located matrix sites containing only fi broblasts and macrophages. Any signs of infl ammatory reaction are observed in connective tissue around the matrix, in developing periosteum, or matrix itself. Th e porous template is invaded by the blood vessels, and loose connective tissue also develops around them. Arteries and veins are detectable both in central and peripheral areas of the porous matrix. Perivascular cells are invading the matrix, along with connective tissue and vessels [4].
Morphological study of the bone/matrix at 3 months post-surgery has shown the entirely organized periosteum consisting of loose connective tissue and dense fi brous tissue. Over this period, the coarse-fi bred connective tissue further expands and fi lls the bone defect. As a next step of bone regeneration, the coarse-fi bred bone tissue and connective tissue periosteum are formed at the 4th month of experiment. At 6 months, the coarse-fibred bone tissue is replaced by a lamellar bone structure. By this term, the regenerating bone has the entirely formed periost represented by loose fibrous and coarse-fi bred connective tissue. The latter is gradually replaced by lamellar bone tissue. However, the repair osteogenesis seems to be incomplete due to predominating coarse-fibred bone tissue. Osteons with narrow Haversian canals are observed in the developing lamellar bone structures.
Conclusion
In the course of experimental study, the porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices. Th ese properties determine some unique characteristics of chitosan, thus enabling its applications in various areas of medicine, especially in dentistry, when performing surgical treatment for infl ammatory periodontal diseases.
Acknowledgements
We are much appreciated to Vladimir E. Yudin and Irina P. Dobrovolskaya for assisting in preparation of this article.
Conflict of interests
The authors have no confl icts of interests to declare.
References
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PV. Development of a new method of surgical treatment of infl ammatory periodontal diseases. Dental Scientifi c and Educational Journal. 2014; 3-4:14. (In Russian)
3. Roach P, Eglin D, Rohde K, Perry CC. Modern biomaterials: a review-bulk properties and implications of surface modifi cations. J Mater Sci Mater Med. 2007; 18(7); 1263-1277.
4. Ulitovskiy S.B., Galibin O.V., Th omson V.V., Antipova A.V. et al. Th e use of surgical techniques in the treatment of infl ammatory periodontal diseases. Scientifi c Notes. 2014;1 (21):71-74. (In Russian).
5. Ulitovskiy S.B., Galibin O.V., Th omson V.V., Antipova A.V. et al. Th e use of diff erent materials in the process of surgical treatment of periodontal disease. Institute of dentistry. 2014; 2(63):100-101. (In Russian).
6. Ulitovskiy S.B., Galibin O.V., Antipova A.V. et al. Application of new technologies in the treatment of periodontal diseases. Dental scientifi c and educational journal. 2013;1/2: 2-5. (In Russian).
7. Muzzarelli RA, Mattioli-Belmonte M, Pugnaloni A, Biagini G. Biochemistry, histology and clinical uses of chitins and chitosans in wound healing. EXS. 1999;87:251-264.
8. Di Martino A, Sittinger M, Risbud MV. Chitosan: a versatile biopolymer for orthopaedic tissue-engineering. Biomaterials. 2005; 26(30): 5983-5990.
9. Yang TL Chitin-based materials in tissue engineering: applications in soft tissue and epithelial organ. Int. J. Mol. Sci. 2011; 12(3):1936-1963.
10. Shi C, Zhu Y, Ran X, Wang M, Su Y, ChengT. Th erapeutic potential of chitosan and its derivatives in regenerative medicine. J Surg Res. 2006;133(2):185-192.
11. Swetha M, Sahithi K, Moorthi A, Srinivasan N, Ramasamy K, Selvamurugan N. Biocomposites containing natural polymers and hydroxyapatite for bone tissue engineering. Int J Biol Macromol. 2010; 47(1):1-4.
12. Chen JP, Chen SH, Lai GJ. Preparation and characterization of biomimetic silk fi broin/chitosan composite nanofi bers by electrospinning for osteoblasts culture. Nanoscale Res Lett. 2012; 7(1):170-178.
13. Biagini G, Pugnaloni A, Damadei A, Bertani A, Belligolli A, Bicchiega V, Muzzarelli R. Morphological study of the capsular organization around tissue expanders coated with N-carboxybutyl chitosan. Biomaterials. 1991; 12(3): 287-291.
14. Venkatesan J, Kim SK. Chitosan composites for bone tissue engineering – an overview. Mar Drugs. 2010; 8(8):2252-2266.
Introduction
Treatment of infl ammatory periodontal diseases (IPD) still represents a lot of issues. Th e global IPD prevalence among adults, according to the WHO data, is up to 90-95% without any trends for decrease [1, 2]. Medical treatment of IPD patients should be performed in combined, purposeful and personalized manner. Both local and general treatment should be applied, using effi cient methods of conservative, surgical and prosthetic treatment [1, 2].
Moreover, some novel treatments are recently introduced, based on cellular engineering, aiming for partial or total replacement of the damaged tissues. Such techniques presume modeling and construction of biocompatible (scaff old-type) carrier containing medical drugs. Th e main requirements for the modern matrix materials are as follows: complete biological compatibility, sustained viability of the cells seeded in the matrix, ability for biodegradation and replacement by normal tissues, changes in structure and properties fi tting the environmental eff ects [3].
Th e tissue engineering techniques are widely used in the IPD surgical treatment, especially when using the so-called directed tissue regeneration (DTR), i.e., a surgical approach which mechanically prevents epithelial migration to the apical side, thus promoting periodontal recovery without usage of natural and synthetic materials for the bone plastics. Th e method is aimed for creation of physical barrier between the graft and treated dental root surface resulting into preferential migration of slowly regenerating periodontal and bone cells to the aff ected site [4].
Both biodegradable and non- biodegradable membranes are now used at the present time when performing the directed tissue regeneration (DTR). Th ey may be classifi ed by their origin and composition, as shown in Table 1. Polytetrafl uorethylene (PTFE) is oft en used for manufacturing the non-biodegradable synthetic membranes. Th e PFTE non-biodegradable membranes are considered a “golden standard” for the DTR methodology. Th e results obtained with other membranes are usually compared to this PFTE material which has several advantages: essential mechanical resistance, no bone fi ller is required, and suffi cient barrier properties are present. PFTE drawbacks include a need for repeated surgical intervention 4 to 6 weeks for its extraction, complete closure of the membrane when sealing the flap with reliable fi xation; a need for regular weekly or biweekly inspections [4, 5, 6].
Table 1. Listing of the main membrane types [5]
Natural membranes represent structures consisting of animal collagen (xenogeneic), or allogeneic membranes which contain allogeneic collagen supplied by lyophilized demineralized bone, or membranes consisting of xenogeneic collagen and reduced amounts of mineral matrix obtained aft er partial electrolytic plate demineralization. All these membranes are based on, mainly, type I collagen. Th eir biodegradation continues for 5 to 6 months, barrier functions retain for 4 months, with good adhesion properties and only rare complications upon their exposure. Such membrane plate is elastic, thus requiring bone plastic materials in order to retain the space. Given long resorption rates, this material should be chosen for defects with presumed slow regeneration. Synthetic membranes are produced as polymeric and gel-like structures. Th e gel membranes are subject to biodegradation within 9 to 12 months, with their barrier properties kept for 6 months. However, it is more diffi cult to work with these materials which are rather hard upon polymerization. This type of membranes is now less common applied in dentistry due to problems when handling them. Th e procedure needs much time in cases of indirect usage, when the membrane is shaped beyond surgical area, followed by introduction to the damaged area [4, 5, 6].
There are no clear benefi ts revealed for either biodegradable, or non-biodegradable membranes. Th erefore, some authors, when comparing parameters of diff erent materials for the membrane fabrication, have considered chitosan to be the most promising substance which exhibits chondro- and osteoconductive properties, high degree of biocompatibility and complete biodegradation of the polymer, as well as expressed antibacterial activity and homeostatic effi ciency [7, 8, 9].
Chitosan is a desialylated form of chitin polymer which is widely spread in living nature. It seems to be a promising raw material for matrices and biomimetics of bone and cartilageous tissues. At the present time, chitosan is increasingly used in dentistry since it meets the requirements for potential matrix base [8, 9, 10].
Chitosan applied as the matrix scaff old allows prevention of immune-related synthesis, thus increasing biocompatibility of the composite matrices. Chemical properties of chitosan provide diff erent modifi cations of its polymer structure, incorporation of various biologically active compounds (both organic and inorganic substances), thus being an important factor. [11, 12, 13, 14]. One should also note that electrostatic and hydrophobic interaction of chitosan with some modifying agents may even enhance its biological activity. Th e aim of this study was to investigate the eff ectiveness of using chitosan membranes for the treatment of infl ammatory periodontal diseases.
Materials and methods
At the present time, we perform a joint study by the Department of Preventive Stomatology, Department of Biotechnology at the R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology (1st St. Petersburg State I. Pavlov Medical University), and the Research Institute of Macromolecular Compounds (Russian Academy of Sciences), concerning development and implementation of an original approach to surgical treatment of infl ammatory periodontal diseases using a novel chitosan-based matrix (Fig. 1), as described elsewhere [6].
Figure 1. A micrograph of chitosan-based matrix was obtained employing Carl Zeiss Supra 55 VP microscopy, magnification 500X. Micrographs (HC. 500X) of chitosan A and B-based membranes were obtained with a Carl Zeiss Supra 55 VP scanning electron microscope
Micrographs A and B are made by P. Popryadukhin
To produce porous membranes, we purchased Chitosan from Fluka Chemie, BioChemika line (molecular mass, 255 kD, deacetylation degree, 80%; ash content, 0.5%). Porous 3-D matrices were obtained by lyophilization of chitosan solution by means of Heto-Holten PowerDry PL9000 -50 device. Before drying, chitosan was dissolved in 2% aqueous solution of acetic acid, at 4 wt%. Th e solvent sublimation in the lyophilizer proceeded for 48 hours. As seen in Fig. 1, pores in the chitosan matrices look like channels, with the diameter of 100 to 150 nm [4].
Th e in vivo experiments with porous chitosan membranes were carried out in rabbits (n=10). Experimental studies were scheduled and performed according to the Guidelines from the Order No.1179 of 10.10.1983, and No.267 of 19.06.2003 issued by the Russian Ministry of Healtcare, European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientifi c Purposes (Strasbourg, 1986), as well as with World Medical Association Declaration of Helsinki (1996).
Table 2 presents the design of experimental study. All surgical interventions proceeded under identical conditions. Th e surgical manipulations were performed under general anesthesia, i.e., Zoletil100, 0.1 mL, and Rometerum (20 mg/mL), 0.0125 mL intravenously.
Two diff erent surgical procedures were performed in rabbits under sterile conditions, aiming for studies of chitosan matrix biocompatibility with adjacent tissues. The surgery was performed in extraoral mode. The operation field was prepared in the right maxillar area. A 5-cm incision was made in maxillar projection, while dissecting the tissue in sharp or blunt way. Aft er accessing the maxilla, an artifi cial bone defect was inflicted, then overlaid by the tested material. Blood coagulation was controlled, and the wound was closed with suture materials layer-by-layer and treated by a tincture of iodine.
Eight rabbits were subjected to the skin and soft tissue incision at the anterior lateral chest surface followed by a rib exposure and infl iction of a bone defect (10 to 12 mm long). The resulting cavity was filled with a biodegradable porous chitosan-based matrix.
Systemic antibacterial therapy was performed during early postsurgical period (3 days) using Gentamycin (single injections of 2.0 mL daily for 3 days). After surgical procedures, the rabbits were placed to individual cages. Th e animals had free access to water and standard diet, being regularly observed. The animals were kept out of experiment, according to the schedule (1 to 6 months aft er the surgical intervention), followed by histological studies of gums and ribs, i.e., the areas of artifi cial bone defects with introduced synthetic materials.
Results
Three months aft er surgery, histological assessment of gingival tissues did not reveal any pathological changes of oral mucosa; the multilayer fl at non-squamous epithelium and underlying connective tissue did not show any signs of inflammatory response (Fig. 2).
Table 2. Experimental study design
Morphological examination of artifi cially damaged ribs with implanted material has revealed multi-component changes of bone tissue and porous matrix. Morphological analysis of the matrix/bone border area has shown a lot of osteoclasts at the site of bone defect 30 days aft er surgery (Fig. 3)
Fibrous connective tissue penetrated by blood vessels is developing between the bone structures and porous template. The matrix is repopulated by fi broblasts and macrophages from local blood vessels and connective tissue, as well as from the developing periosteal layer. The entire porous matrix is occupied by connective tissue cells by 30 days of experiment. The intra-matrix fi broblasts are actively producing intercellular components of connective tissue. Due to biodegradation of the matrix and phagocytic activity of macrophages, the microcavities are formed which become larger than initial pores. Hence, the matrix pores and newly developing cavities become surrounded by connective tissue structures containing big amounts of collagen fi bers and cell composition typical to the fi brous connective tissue. Moreover, the implant areas adjacent to newly formed periosteum, are more rich in connective tissue, as compared to the more centrally located matrix sites containing only fi broblasts and macrophages. Any signs of infl ammatory reaction are observed in connective tissue around the matrix, in developing periosteum, or matrix itself. Th e porous template is invaded by the blood vessels, and loose connective tissue also develops around them. Arteries and veins are detectable both in central and peripheral areas of the porous matrix. Perivascular cells are invading the matrix, along with connective tissue and vessels [4].
Morphological study of the bone/matrix at 3 months post-surgery has shown the entirely organized periosteum consisting of loose connective tissue and dense fi brous tissue. Over this period, the coarse-fi bred connective tissue further expands and fi lls the bone defect. As a next step of bone regeneration, the coarse-fi bred bone tissue and connective tissue periosteum are formed at the 4th month of experiment. At 6 months, the coarse-fibred bone tissue is replaced by a lamellar bone structure. By this term, the regenerating bone has the entirely formed periost represented by loose fibrous and coarse-fi bred connective tissue. The latter is gradually replaced by lamellar bone tissue. However, the repair osteogenesis seems to be incomplete due to predominating coarse-fibred bone tissue. Osteons with narrow Haversian canals are observed in the developing lamellar bone structures.
Conclusion
In the course of experimental study, the porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices. Th ese properties determine some unique characteristics of chitosan, thus enabling its applications in various areas of medicine, especially in dentistry, when performing surgical treatment for infl ammatory periodontal diseases.
Acknowledgements
We are much appreciated to Vladimir E. Yudin and Irina P. Dobrovolskaya for assisting in preparation of this article.
Conflict of interests
The authors have no confl icts of interests to declare.
References
1. Antipova AV, Suslov DN, Yukina GYu, Popryadukhin PV. Use of resorbed membranes for surgical treatment of inflammatory diseases of the periodontium. Dental Scientific and Educational Journal. 2014; 1-2:16-17. (In Russian) 2. Antipova AV, Suslov DN, Yukina GYu, Popryadukhin
PV. Development of a new method of surgical treatment of infl ammatory periodontal diseases. Dental Scientifi c and Educational Journal. 2014; 3-4:14. (In Russian)
3. Roach P, Eglin D, Rohde K, Perry CC. Modern biomaterials: a review-bulk properties and implications of surface modifi cations. J Mater Sci Mater Med. 2007; 18(7); 1263-1277.
4. Ulitovskiy S.B., Galibin O.V., Th omson V.V., Antipova A.V. et al. Th e use of surgical techniques in the treatment of infl ammatory periodontal diseases. Scientifi c Notes. 2014;1 (21):71-74. (In Russian).
5. Ulitovskiy S.B., Galibin O.V., Th omson V.V., Antipova A.V. et al. Th e use of diff erent materials in the process of surgical treatment of periodontal disease. Institute of dentistry. 2014; 2(63):100-101. (In Russian).
6. Ulitovskiy S.B., Galibin O.V., Antipova A.V. et al. Application of new technologies in the treatment of periodontal diseases. Dental scientifi c and educational journal. 2013;1/2: 2-5. (In Russian).
7. Muzzarelli RA, Mattioli-Belmonte M, Pugnaloni A, Biagini G. Biochemistry, histology and clinical uses of chitins and chitosans in wound healing. EXS. 1999;87:251-264.
8. Di Martino A, Sittinger M, Risbud MV. Chitosan: a versatile biopolymer for orthopaedic tissue-engineering. Biomaterials. 2005; 26(30): 5983-5990.
9. Yang TL Chitin-based materials in tissue engineering: applications in soft tissue and epithelial organ. Int. J. Mol. Sci. 2011; 12(3):1936-1963.
10. Shi C, Zhu Y, Ran X, Wang M, Su Y, ChengT. Th erapeutic potential of chitosan and its derivatives in regenerative medicine. J Surg Res. 2006;133(2):185-192.
11. Swetha M, Sahithi K, Moorthi A, Srinivasan N, Ramasamy K, Selvamurugan N. Biocomposites containing natural polymers and hydroxyapatite for bone tissue engineering. Int J Biol Macromol. 2010; 47(1):1-4.
12. Chen JP, Chen SH, Lai GJ. Preparation and characterization of biomimetic silk fi broin/chitosan composite nanofi bers by electrospinning for osteoblasts culture. Nanoscale Res Lett. 2012; 7(1):170-178.
13. Biagini G, Pugnaloni A, Damadei A, Bertani A, Belligolli A, Bicchiega V, Muzzarelli R. Morphological study of the capsular organization around tissue expanders coated with N-carboxybutyl chitosan. Biomaterials. 1991; 12(3): 287-291.
14. Venkatesan J, Kim SK. Chitosan composites for bone tissue engineering – an overview. Mar Drugs. 2010; 8(8):2252-2266.
* Кафедра стоматологии профилактической
** Отдел биотехнологии Института детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой
*** Лаборатория патоморфологии НИЦ
**** Лаборатория инвазивных технологий НИЦ, ПСПбГМУ" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20905" ["VALUE"]=> array(2) { ["TEXT"]=> string(687) "<sup>1</sup> Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова МЗ РФ (ПСПбГМУ), Санкт-Петербург, Россия<br> <sup>2</sup> Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия<br> <sup>3</sup> ФГБУ «Российский научный центр радиологии и хирургических технологий им. акад. А.М. Гранова» МЗ РФ, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(639) "1 Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова МЗ РФ (ПСПбГМУ), Санкт-Петербург, Россия
2 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
3 ФГБУ «Российский научный центр радиологии и хирургических технологий им. акад. А.М. Гранова» МЗ РФ, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20906" ["VALUE"]=> array(2) { ["TEXT"]=> string(3603) "<p style="text-align: justify;"> На сегодняшний день существует большое количество методов лечения воспалительных заболеваний пародонта, являющихся самыми распространенными стоматологическими заболеваниями в мире. Описывается метод хирургического лечения воспалительных заболеваний пародонта, приводится классификация природных и синтетических мембран, использующихся при хирургическом методе лечения, приводится новая технология с использованием природного полимера хитозана. </p> <h2 style="text-align: justify;">Материалы и методы</h2> <p style="text-align: justify;"> Пористые трехмерные матрицы получали путем лиофилизации хитозана из 2% раствора уксусной кислоты. Полученные матрицы из хитозана содержали микропоры размером 100-150 нм. Эксперименты in vivo с пористыми хитозановыми мембранами проводили на кроликах. Животным наносили искусственные дефекты максиллярной кости и покрывали их испытуемым материалом. Некоторым животным наносили повреждение ребра, которое потом заполняли биодеградируемой матрицей из пористого хитозана. </p> <h2 style="text-align: justify;">Результаты</h2> <p style="text-align: justify;"> Морфологическое исследование искусственно поврежденных ребер с имплантированным материалом выявило разнообразные изменения костной ткани и пористой матрицы без существенных признаков воспаления. Спустя 1 мес., на границе кости и матрицы отмечены остеокластическая реакция наряду с неоангиогенезом в зоне костного дефекта. Через 3-6 мес. после хирургического вмешательства образовались периостальные структуры, а также зоны локального фиброза </p> <h2 style="text-align: justify;">Выводы</h2> <p style="text-align: justify;"> Пористые хитозановые матрицы оказались биосовместимым, биоинертным и биорезорбируемым материалом, что соответствует критериям, применимым к материалам для производства костных матриц. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Пародонт, регенерация, мембрана, хитозан. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3405) "
На сегодняшний день существует большое количество методов лечения воспалительных заболеваний пародонта, являющихся самыми распространенными стоматологическими заболеваниями в мире. Описывается метод хирургического лечения воспалительных заболеваний пародонта, приводится классификация природных и синтетических мембран, использующихся при хирургическом методе лечения, приводится новая технология с использованием природного полимера хитозана.
Материалы и методы
Пористые трехмерные матрицы получали путем лиофилизации хитозана из 2% раствора уксусной кислоты. Полученные матрицы из хитозана содержали микропоры размером 100-150 нм. Эксперименты in vivo с пористыми хитозановыми мембранами проводили на кроликах. Животным наносили искусственные дефекты максиллярной кости и покрывали их испытуемым материалом. Некоторым животным наносили повреждение ребра, которое потом заполняли биодеградируемой матрицей из пористого хитозана.
Результаты
Морфологическое исследование искусственно поврежденных ребер с имплантированным материалом выявило разнообразные изменения костной ткани и пористой матрицы без существенных признаков воспаления. Спустя 1 мес., на границе кости и матрицы отмечены остеокластическая реакция наряду с неоангиогенезом в зоне костного дефекта. Через 3-6 мес. после хирургического вмешательства образовались периостальные структуры, а также зоны локального фиброза
Выводы
Пористые хитозановые матрицы оказались биосовместимым, биоинертным и биорезорбируемым материалом, что соответствует критериям, применимым к материалам для производства костных матриц.
Ключевые слова
Пародонт, регенерация, мембрана, хитозан.
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1** Biotechnology Department, R.Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation
1*** Laboratory of Pathomorphology, Th e University Research Center
1**** Laboratory of Invasive Technologies, Th e University Research Center" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20909" ["VALUE"]=> array(2) { ["TEXT"]=> string(311) "<sup>1</sup> First Petersburg State I. Pavlov Medical University<br> <sup>2</sup> Institute of Macromolecular Compounds, Russian Academy of Sciences<br> <sup>3</sup> Russian Research A.Granov Center of Radiology and Surgical Technologies, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(263) "1 First Petersburg State I. Pavlov Medical University
2 Institute of Macromolecular Compounds, Russian Academy of Sciences
3 Russian Research A.Granov Center of Radiology and Surgical Technologies, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20910" ["VALUE"]=> array(2) { ["TEXT"]=> string(2191) "<p style="text-align: justify;"> A variety of medications is applied nowadays for treatment of infl ammatory periodontal diseases (IPD) which are the prevalent dental disorders worldwide. A method of surgical treatment is described for IPD. We present a classifi cation of natural and synthetic membranes used in surgical interventions, and describe a novel treatment technology using a natural chitosan polymer. </p> <h2 style="text-align: justify;">Materials and methods</h2> <p style="text-align: justify;"> Porous 3-D matrices were obtained by lyophilization of chitosan solution from the 2% solution of acetic acid. Th e resulting chitosan matrices had micropores of 100 to 150 nm in size. Th e in vivo experiments with porous chitosan membranes were performed in rabbits. Artificial maxillar bone defects were infl icted, being overlaidby the tested material. Some animals were subjected to rib exposure and infl iction of a bone defect, then filled with a biodegradable porous chitosan-based matrix. </p> <h2 style="text-align: justify;">Results</h2> <p style="text-align: justify;"> Morphological examination of artifi cially damaged ribs with implanted material has revealed various changes of bone tissue and porous matrix, without suffi cient inflammation signs. At 1 month, the matrix/bone border has shown osteoclasts at the site of bone defect 30 days aft er surgery, along with neoangiogenesis at the site of repair. At 3 to 6 months post-surgery, periosteal structures were organized, as well as local fi brosis was developed. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> Porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Periodontium, regeneration, membrane, chitosan. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1993) "
A variety of medications is applied nowadays for treatment of infl ammatory periodontal diseases (IPD) which are the prevalent dental disorders worldwide. A method of surgical treatment is described for IPD. We present a classifi cation of natural and synthetic membranes used in surgical interventions, and describe a novel treatment technology using a natural chitosan polymer.
Materials and methods
Porous 3-D matrices were obtained by lyophilization of chitosan solution from the 2% solution of acetic acid. Th e resulting chitosan matrices had micropores of 100 to 150 nm in size. Th e in vivo experiments with porous chitosan membranes were performed in rabbits. Artificial maxillar bone defects were infl icted, being overlaidby the tested material. Some animals were subjected to rib exposure and infl iction of a bone defect, then filled with a biodegradable porous chitosan-based matrix.
Results
Morphological examination of artifi cially damaged ribs with implanted material has revealed various changes of bone tissue and porous matrix, without suffi cient inflammation signs. At 1 month, the matrix/bone border has shown osteoclasts at the site of bone defect 30 days aft er surgery, along with neoangiogenesis at the site of repair. At 3 to 6 months post-surgery, periosteal structures were organized, as well as local fi brosis was developed.
Conclusion
Porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices.
Keywords
Periodontium, regeneration, membrane, chitosan.
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Ulitovskiy <sup>1</sup><sup>*</sup>, Anna V. Antipova <sup>1</sup><sup>*</sup>, Alexander D. Vilesov <sup>1</sup><sup>*</sup><sup>*</sup>, <sup>2</sup>, GalinaYu. Yukina <sup>1</sup><sup>*</sup><sup>*</sup><sup>*</sup>, Dmitry N. Suslov <sup>1</sup><sup>*</sup><sup>*</sup><sup>*</sup><sup>*</sup>, <sup>3</sup>, Pavel V. Popryadukhin <sup>1</sup><sup>*</sup><sup>*</sup><sup>*</sup><sup>*</sup>, <sup>2</sup>, Oleg V. Galibin <sup>1</sup><sup>*</sup><sup>*<br> </sup><sup>1</sup><sup>*</sup> Department of Preventive Stomatology<br> <sup>1</sup><sup>*</sup><sup>*</sup> Biotechnology Department, R.Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation<br> <sup>1</sup><sup>*</sup><sup>*</sup><sup>*</sup> Laboratory of Pathomorphology, Th e University Research Center<br> <sup>1</sup><sup>*</sup><sup>*</sup><sup>*</sup><sup>*</sup> Laboratory of Invasive Technologies, Th e University Research Center" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(957) "Sergey B. Ulitovskiy 1*, Anna V. Antipova 1*, Alexander D. Vilesov 1**, 2, GalinaYu. Yukina 1***, Dmitry N. Suslov 1****, 3, Pavel V. Popryadukhin 1****, 2, Oleg V. Galibin 1**1* Department of Preventive Stomatology
1** Biotechnology Department, R.Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation
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1* Department of Preventive Stomatology
1** Biotechnology Department, R.Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation
1*** Laboratory of Pathomorphology, Th e University Research Center
1**** Laboratory of Invasive Technologies, Th e University Research Center" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20910" ["VALUE"]=> array(2) { ["TEXT"]=> string(2191) "<p style="text-align: justify;"> A variety of medications is applied nowadays for treatment of infl ammatory periodontal diseases (IPD) which are the prevalent dental disorders worldwide. A method of surgical treatment is described for IPD. We present a classifi cation of natural and synthetic membranes used in surgical interventions, and describe a novel treatment technology using a natural chitosan polymer. </p> <h2 style="text-align: justify;">Materials and methods</h2> <p style="text-align: justify;"> Porous 3-D matrices were obtained by lyophilization of chitosan solution from the 2% solution of acetic acid. Th e resulting chitosan matrices had micropores of 100 to 150 nm in size. Th e in vivo experiments with porous chitosan membranes were performed in rabbits. Artificial maxillar bone defects were infl icted, being overlaidby the tested material. Some animals were subjected to rib exposure and infl iction of a bone defect, then filled with a biodegradable porous chitosan-based matrix. </p> <h2 style="text-align: justify;">Results</h2> <p style="text-align: justify;"> Morphological examination of artifi cially damaged ribs with implanted material has revealed various changes of bone tissue and porous matrix, without suffi cient inflammation signs. At 1 month, the matrix/bone border has shown osteoclasts at the site of bone defect 30 days aft er surgery, along with neoangiogenesis at the site of repair. At 3 to 6 months post-surgery, periosteal structures were organized, as well as local fi brosis was developed. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> Porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Periodontium, regeneration, membrane, chitosan. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1993) "
A variety of medications is applied nowadays for treatment of infl ammatory periodontal diseases (IPD) which are the prevalent dental disorders worldwide. A method of surgical treatment is described for IPD. We present a classifi cation of natural and synthetic membranes used in surgical interventions, and describe a novel treatment technology using a natural chitosan polymer.
Materials and methods
Porous 3-D matrices were obtained by lyophilization of chitosan solution from the 2% solution of acetic acid. Th e resulting chitosan matrices had micropores of 100 to 150 nm in size. Th e in vivo experiments with porous chitosan membranes were performed in rabbits. Artificial maxillar bone defects were infl icted, being overlaidby the tested material. Some animals were subjected to rib exposure and infl iction of a bone defect, then filled with a biodegradable porous chitosan-based matrix.
Results
Morphological examination of artifi cially damaged ribs with implanted material has revealed various changes of bone tissue and porous matrix, without suffi cient inflammation signs. At 1 month, the matrix/bone border has shown osteoclasts at the site of bone defect 30 days aft er surgery, along with neoangiogenesis at the site of repair. At 3 to 6 months post-surgery, periosteal structures were organized, as well as local fi brosis was developed.
Conclusion
Porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices.
Keywords
Periodontium, regeneration, membrane, chitosan.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1993) "A variety of medications is applied nowadays for treatment of infl ammatory periodontal diseases (IPD) which are the prevalent dental disorders worldwide. A method of surgical treatment is described for IPD. We present a classifi cation of natural and synthetic membranes used in surgical interventions, and describe a novel treatment technology using a natural chitosan polymer.
Materials and methods
Porous 3-D matrices were obtained by lyophilization of chitosan solution from the 2% solution of acetic acid. Th e resulting chitosan matrices had micropores of 100 to 150 nm in size. Th e in vivo experiments with porous chitosan membranes were performed in rabbits. Artificial maxillar bone defects were infl icted, being overlaidby the tested material. Some animals were subjected to rib exposure and infl iction of a bone defect, then filled with a biodegradable porous chitosan-based matrix.
Results
Morphological examination of artifi cially damaged ribs with implanted material has revealed various changes of bone tissue and porous matrix, without suffi cient inflammation signs. At 1 month, the matrix/bone border has shown osteoclasts at the site of bone defect 30 days aft er surgery, along with neoangiogenesis at the site of repair. At 3 to 6 months post-surgery, periosteal structures were organized, as well as local fi brosis was developed.
Conclusion
Porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices.
Keywords
Periodontium, regeneration, membrane, chitosan.
" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20907" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2018-7-4-66-71" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2018-7-4-66-71" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2018-7-4-66-71" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20911" ["VALUE"]=> string(79) "Surgical treatment of inflammatory periodontal diseases using chitosan matrices" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(79) "Surgical treatment of inflammatory periodontal diseases using chitosan matrices" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(79) "Surgical treatment of inflammatory periodontal diseases using chitosan matrices" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20909" ["VALUE"]=> array(2) { ["TEXT"]=> string(311) "<sup>1</sup> First Petersburg State I. Pavlov Medical University<br> <sup>2</sup> Institute of Macromolecular Compounds, Russian Academy of Sciences<br> <sup>3</sup> Russian Research A.Granov Center of Radiology and Surgical Technologies, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(263) "1 First Petersburg State I. Pavlov Medical University2 Institute of Macromolecular Compounds, Russian Academy of Sciences
3 Russian Research A.Granov Center of Radiology and Surgical Technologies, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(263) "1 First Petersburg State I. Pavlov Medical University
2 Institute of Macromolecular Compounds, Russian Academy of Sciences
3 Russian Research A.Granov Center of Radiology and Surgical Technologies, St. Petersburg, Russia" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20904" ["VALUE"]=> array(2) { ["TEXT"]=> string(1614) "Сергей Б. Улитовский <sup>1</sup><sup>*</sup><sup>*</sup>, Анна В. Антипова <sup>1</sup><sup>*</sup>, Александр Д. Вилесов <sup>1</sup><sup>*</sup><sup>*</sup>, <sup>2</sup>, Галина Ю. Юкина <sup>1</sup><sup>*</sup><sup>*</sup><sup>*</sup>, Дмитрий Н. Суслов <sup>1</sup><sup>*</sup><sup>*</sup><sup>*</sup><sup>*</sup>, <sup>3</sup>, Павел В. Попрядухин <sup>1</sup><sup>*</sup><sup>*</sup><sup>*</sup><sup>*</sup>, <sup>2</sup>, Олег В. Галибин <sup>1</sup><sup>*</sup><sup>*<br> </sup><sup>*</sup> Кафедра стоматологии профилактической<br> <sup>*</sup><sup>*</sup> Отдел биотехнологии Института детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой<br> <sup>*</sup><sup>*</sup><sup>*</sup> Лаборатория патоморфологии НИЦ<br> <sup>*</sup><sup>*</sup><sup>*</sup><sup>*</sup> Лаборатория инвазивных технологий НИЦ, ПСПбГМУ" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1134) "Сергей Б. Улитовский 1**, Анна В. Антипова 1*, Александр Д. Вилесов 1**, 2, Галина Ю. Юкина 1***, Дмитрий Н. Суслов 1****, 3, Павел В. Попрядухин 1****, 2, Олег В. Галибин 1**
* Кафедра стоматологии профилактической
** Отдел биотехнологии Института детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой
*** Лаборатория патоморфологии НИЦ
**** Лаборатория инвазивных технологий НИЦ, ПСПбГМУ" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1134) "Сергей Б. Улитовский 1**, Анна В. Антипова 1*, Александр Д. Вилесов 1**, 2, Галина Ю. Юкина 1***, Дмитрий Н. Суслов 1****, 3, Павел В. Попрядухин 1****, 2, Олег В. Галибин 1**
* Кафедра стоматологии профилактической
** Отдел биотехнологии Института детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой
*** Лаборатория патоморфологии НИЦ
**** Лаборатория инвазивных технологий НИЦ, ПСПбГМУ" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20906" ["VALUE"]=> array(2) { ["TEXT"]=> string(3603) "<p style="text-align: justify;"> На сегодняшний день существует большое количество методов лечения воспалительных заболеваний пародонта, являющихся самыми распространенными стоматологическими заболеваниями в мире. Описывается метод хирургического лечения воспалительных заболеваний пародонта, приводится классификация природных и синтетических мембран, использующихся при хирургическом методе лечения, приводится новая технология с использованием природного полимера хитозана. </p> <h2 style="text-align: justify;">Материалы и методы</h2> <p style="text-align: justify;"> Пористые трехмерные матрицы получали путем лиофилизации хитозана из 2% раствора уксусной кислоты. Полученные матрицы из хитозана содержали микропоры размером 100-150 нм. Эксперименты in vivo с пористыми хитозановыми мембранами проводили на кроликах. Животным наносили искусственные дефекты максиллярной кости и покрывали их испытуемым материалом. Некоторым животным наносили повреждение ребра, которое потом заполняли биодеградируемой матрицей из пористого хитозана. </p> <h2 style="text-align: justify;">Результаты</h2> <p style="text-align: justify;"> Морфологическое исследование искусственно поврежденных ребер с имплантированным материалом выявило разнообразные изменения костной ткани и пористой матрицы без существенных признаков воспаления. Спустя 1 мес., на границе кости и матрицы отмечены остеокластическая реакция наряду с неоангиогенезом в зоне костного дефекта. Через 3-6 мес. после хирургического вмешательства образовались периостальные структуры, а также зоны локального фиброза </p> <h2 style="text-align: justify;">Выводы</h2> <p style="text-align: justify;"> Пористые хитозановые матрицы оказались биосовместимым, биоинертным и биорезорбируемым материалом, что соответствует критериям, применимым к материалам для производства костных матриц. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Пародонт, регенерация, мембрана, хитозан. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3405) "
На сегодняшний день существует большое количество методов лечения воспалительных заболеваний пародонта, являющихся самыми распространенными стоматологическими заболеваниями в мире. Описывается метод хирургического лечения воспалительных заболеваний пародонта, приводится классификация природных и синтетических мембран, использующихся при хирургическом методе лечения, приводится новая технология с использованием природного полимера хитозана.
Материалы и методы
Пористые трехмерные матрицы получали путем лиофилизации хитозана из 2% раствора уксусной кислоты. Полученные матрицы из хитозана содержали микропоры размером 100-150 нм. Эксперименты in vivo с пористыми хитозановыми мембранами проводили на кроликах. Животным наносили искусственные дефекты максиллярной кости и покрывали их испытуемым материалом. Некоторым животным наносили повреждение ребра, которое потом заполняли биодеградируемой матрицей из пористого хитозана.
Результаты
Морфологическое исследование искусственно поврежденных ребер с имплантированным материалом выявило разнообразные изменения костной ткани и пористой матрицы без существенных признаков воспаления. Спустя 1 мес., на границе кости и матрицы отмечены остеокластическая реакция наряду с неоангиогенезом в зоне костного дефекта. Через 3-6 мес. после хирургического вмешательства образовались периостальные структуры, а также зоны локального фиброза
Выводы
Пористые хитозановые матрицы оказались биосовместимым, биоинертным и биорезорбируемым материалом, что соответствует критериям, применимым к материалам для производства костных матриц.
Ключевые слова
Пародонт, регенерация, мембрана, хитозан.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3405) "На сегодняшний день существует большое количество методов лечения воспалительных заболеваний пародонта, являющихся самыми распространенными стоматологическими заболеваниями в мире. Описывается метод хирургического лечения воспалительных заболеваний пародонта, приводится классификация природных и синтетических мембран, использующихся при хирургическом методе лечения, приводится новая технология с использованием природного полимера хитозана.
Материалы и методы
Пористые трехмерные матрицы получали путем лиофилизации хитозана из 2% раствора уксусной кислоты. Полученные матрицы из хитозана содержали микропоры размером 100-150 нм. Эксперименты in vivo с пористыми хитозановыми мембранами проводили на кроликах. Животным наносили искусственные дефекты максиллярной кости и покрывали их испытуемым материалом. Некоторым животным наносили повреждение ребра, которое потом заполняли биодеградируемой матрицей из пористого хитозана.
Результаты
Морфологическое исследование искусственно поврежденных ребер с имплантированным материалом выявило разнообразные изменения костной ткани и пористой матрицы без существенных признаков воспаления. Спустя 1 мес., на границе кости и матрицы отмечены остеокластическая реакция наряду с неоангиогенезом в зоне костного дефекта. Через 3-6 мес. после хирургического вмешательства образовались периостальные структуры, а также зоны локального фиброза
Выводы
Пористые хитозановые матрицы оказались биосовместимым, биоинертным и биорезорбируемым материалом, что соответствует критериям, применимым к материалам для производства костных матриц.
Ключевые слова
Пародонт, регенерация, мембрана, хитозан.
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Introduction
Erythropoietin (EPO) was initially known as a physiological growth factor which is produced, mainly, by renal glomeruli, macrophages and some other cell types. EPO is shown to support survival and mitotic activity, as well as inhibit apoptosis of late erythroid precursor cells in bone marrow [1]. Th erefore, recombinant erythropoietins-alpha (Eprex, Epobioicrine, Epostim etc.) are widely used to correct anemias in diff erent diseases and posttransplant conditions [2].
However, biological mechanisms of EPO action upon immune cells are still not clear. E.g., antioxidant in vivo eff ects of EPO (reduced lipid peroxidation in blood lymphocytes) are shown by Osikov et al. [3]. Immunotropic eff ects of EPO are recently studied, due to its immunomodulatory eff ects under clinical and experimental conditions [4-6]. Response of lymphocytes and macrophages to EPO seems to be mediated by the EPO receptors on their surface [7]. In vitro biological eff ects of EPO towards T-lymphoid cells were previously shown by Hisatomi et al. [8] who demonstrated suppression of IL-2 gene expression in TLC cells after their short-term (6 h) incubation with EPO. Hence, EPO is able to exert fast immediate action upon T-lymphoid cells over short incubation terms. Indeed, we have also revealed modulatory effect of EPO upon rat thymocytes using a specifi c potential-sensitive chemical probe [9]. EPO was found to exert activating eff ect upon the TLC by changing total transmembrane potential of plasmatic (Δφp) and mitochondrial membranes (Δφm). This activation correlated with increased numbers of the probe-labeled fl uorescent mitochondria in exposed cells [10]. To discern these mechanisms, we used specifi c inhibitors of oxydative phosphorylation, in order to assess the type of potential responsible for these EPO eff ects. Hence, the aim of this work was to evaluate the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes in order to specify this response to EPO, either Δφm, or Δφp. To address this issue, we used specifi c inhbitors of phosphorylation in the respiratory chain which serve as important tools for studying energy supply in the living cells.
To address this issue, we used specifi c inhibitors of oxydative phosphorylation. In order to evaluate the role of mitochondrial functions for energy supply in thymic lymphocytes exposed to EPO. Hence, the aim of this study was to assess a restoring EPO eff ect upon the in vitro response of thymocytes aft er treatment with diff erent specifi c inhibitors of oxidative phosphorylation.
Materials and Methods
We have studied lymphoid cells isolated from thymuses of white Wistar rats (200-300 g), aft er gentle mincing of thymus glands [9]. Th e cells were resuspended in standard Hank’s solution at 2 to 3x107 cells/mL. Percentage of viable (dye-excluding) cells was determined by routine Trypan Blue staining.
To determine possible points for EPO actions, we used different inhibitors of the oxidative phosphorylation, i.e., dinitrophenol (DNP, Sigma, USA), an inhibitor of respiratory chain and uncoupler of oxidative phosphorylation; pentachlorophenol (PCP, Sigma USA), an uncoupler of oxidative phosphorylation; dicyclohexyl carbodiimide (DCCD, Sigma, USA), an inhibitor of mitochondrial membrane-bound ATP-ase domain. Erythropoietin (EPO) was purchased from Cilag (Eprex) was dissolved in Hank’s solution. A potential- sensitive fl uorescent probe [4-(p-dimethylaminostyryl)- 1-methylpyridinium] (DSM) was used to test the energy potential of cells. DSM was produced and purchased from the Latvian Institute of Organic Synthesis [9]. Th e thymocyte suspensions in Eppendorf-type tubes were pre-incubated with inhibitors for 10…20…40 min at 37°С, then EPO was added at the fi nal concentration of 2U/ml), followed by incubation for 30 min, addition of the DSM probe (1.5 μM), and post-incubated for 20 min. Final concentrations of inhibitors were as follows: DNP, 0.1 mM; PCP, 1.5 μM; DCCD, 0.1 mM, at a v/v ratio of <5% to the initial suspension volume. The control samples of cells were supplied with equal volumes of Hanks’ solution, and, aft er 10…30 min. at 37°С, were incubated with DSM and EPO, as described above. Control and experimental TLC samples were then studied at the luminescent microscope LUMAM – R8 (LOMO, St. Petersburg, Russia) at a 900x magnifi cation, using a temperature-controlled stage for the count chamber. Th e fl uorescence was excited by a mercury lamp (λ= 405-436 nm). To measure light emission, a FMEL-1 photometric device was used, with an interference fi lter with a maximum transmission at 585 nm. Fluorescence intensity was manually measured for single cells localized in the vision fi eld, then transformed to a digital signal. Th e numbers of DSM-stained bright mitochondria, looking as intracellular yellow granules, were counted per each single cell (the nm/c values) [9]. Fift y to seventy cells were studied per sample, and the mean fl uorescence intensity was calculated as conventional units (F̃, arbitrary units). The fluorescent signal did not quench over the measurement time. Photomicrographs of the DSM-stained cells were performed with a TSA 5.0 camera mounted in the LOMO R8 microscope, and analyzed by a Microanalysis View soft ware (from the same manufacturer). Statistical evaluation of the data was performed by the Spearmen range correlation criterion. A total of 8,000 cells have been studied in 160 samples. Each independent experiment included 3 to 5 measure points.
Results
Initial amount of intact thymic lymphoid cells in cell suspensions was 92 to 96%. Several control experiments with have shown a decrease of nm/c and F̃ values for these cells aft er incubation with either inhibitor. Th e degree of such decrease depended on the type of inhibiting substance, and incubation terms (Table 1, Fig. 1 A, B, C). Th e most pronounced and faster eff ect was observed with DNP, i.e., fl uorescent mitochondria became virtually absent in DNP-treated cells as soon as aft er 10 min of exposure. F̃ values were also decreased by 20 min, with both nm/c and F̃ reduction. Fluorescent mitochondria disappeared by 40 min, with F̃ at the background levels. EPO addition did not restore F̃ and nm/c- parameters. Th e dynamics of thymocytes with absent mitochondrial fl uorescence aft er DNP exposure shown in Fig. 1A (NC-EM,%), like as absence of recovery aft er EPO addition. Th is eff ect may be caused by classical protonophore properties of DNP which irreversibly reduces both mentioned components of electrochemical gradient, thus causing the mitochondrial membrane depolarization.
Table 1. Time-dependent changes of mean fluorescence (F, arb. units) and number of fluorescent mitochondria per one cell (nm/c) upon short-term exposure of rat TLC to respiratory chain inhibitors followed by EPO treatment
Note: * – P< 0.01; ** – P< 0.025; nm/c – mean number of fl uorescent mitochondria per cell; F̃, arb. units – mean fl uorescence levels for all the cell measured at the given time points. Controls: TLC incubated without inhibitors at 37°С, with EPO supplied aft er 40 min. of incubation. Experimental samples: cells with addition of DNP, or PCP, or DCCD followed by incubation with EPO at 37°С. Mean values (M) and mean error (m) are shown for each time point
Similar, but less pronounced decrease was observed 10 min aft er treatment with PCP, i.e., n m/c dropped by 37%, and F̃, by ~ 35%. Following 20-min incubation, we observed only ~ 26% nm/c and ~ 25% F̃ of control values. At 40 min., no fl uorescent mitochondria are seen.
Meanwhile, Fig. 1B shows increase of non-fl uorescent cell numbers (NC-EM, %) induced by PCP, followed by a recovery induced by EPO supplement. The inhibitory effect of PCP upon thymocytes proved to be partially reversible aft er addition of EPO (nm/c recovery by ~23%, and F̃ values by ~20%).
A 10-min. incubation of thymocytes with DCCD again retains only a part of fl uorescent cells (nm/c, 30%, and ~33% F̃). Only 18% nm/c and ~ 20% F̃ remain aft er 20 min. with DCCD, a mitochondrial membrane-bound ATP-ase. At 40 min. with DCDD, no fl uorescence was observed in the cells, with background F̃ values. However, 30-min. incubation with EPO has resulted into recovery of mitochondria-associated fl uorescence to 42% for nm/c and 38% for F̃ levels, as compared with control samples. Fig. 1C illustrates the dynamics (NC-EM, %) of de-energized thymocytes induced by DCCD followed by restoration of potential-coupled fl uorescence aft er EPO treatment.
Typical patterns of DSM-stained cells before and aft er treatment with mitochondrial ATP-ase inhibitor (DCCD) are shown in Fig. 2 A-C.
Figure 1. Changing amounts of rat thymic lymphocytes devoid of fluorescent mitochondria (NC-EM, %) from initial
time points (0 min.), following incubation with different inhibitors, and after EPO addition. Incubation at 37°C with
DNP (Fig. 1A); PCP (Fig. 1B); DCCD (Fig. 1C) was followed by uniform exposure to EPO. Abscissa: incubation terms (min);
ordinate, mean values of TLC without fluorescent mitochondria (NC-EM, %) for each time point. Vertical bars show
appropriate confidence intervals for P<0.05 as compared to initial values
Figure 2. Rat thymocytes stained with a fluorescent DSM probe. 2A, an original sample after incubation with EPO,
F=52,0 arb. units; 2B, cells after 40 min of incubation with DCCD, F=3,0 arb. units; 2C, thymocytes after exposure of
DCCD-treated cells to EPO, F=20,0 arb. units
Discussion
In our works, we have used inhibitor analysis, in order to assess the mechanisms which regulate anti-apoptotic eff ects of erythropoietin. Th e transmembrane potential of membranes in thymocytes was determined as fl uorescence intensity of DSM probe. Total DSM fl uorescence depends on a summary potentials of plasmatic and mitochondrial membranes. Earlier we have found that EPO acts upon thymic lymphoid cells by changing electric charge of cellular membranes. Th e EPO stimulatory eff ect is accompanied by increased nm/c, due to proton potential (Δφm), and/or external membrane potential (Δφp) [9].
Our data suggest that some metabolic eff ects of EPO are exerted via mitochondrial respiratory pathways. EPO was shown to reverse the de-energizing eff ects of DCCD, thus presuming functional changes of F0F1 membrane ATP which is specifi cally inhibited by the DCCD.
The mitochondrial F0F1-ATP-ase is a complex lipoprotein containing of hydrophilic catalytic center (F1), and a membrane domain (F0) [11]. DCDD used in this work is a specific proton translocation inhibitor in the F0F1 ATP-ase [12], causing decrease in nm/c and general F̃ shown in our experiments, thus refl ecting a critical role of ATP-ase for sustaining the mitochondrial membrane potential. Th e reduced fl uorescence of DSM-induced mitochondria could be considered as mitochondrial de-energization, which proved to be reversible by EPO treatment. Th is fi nding may refl ect ability of EPO to restore functional integrity of mitochondrial membranes as a component of their eff ects upon immune system. The restored mitochondrial functions in the target cells for EPO allow to perform regulatory signaling in lymphoid cells, e.g., via phosphorylation of some transcription factors, e.g., STAT5 in lymphoid cells and tissues [13]. Further studies in other lymphoid cell models could further elucidate the role of EPO as a regulator of mitochondrial function.
Conclusions
1. Thymocytes may represent a non-usual, but suitable model for evaluation of growth factor eff ects upon dividing, apoptosis- prone immune cells.
2. The in vitro testing of modifying EPO eff ects in thymocytes exposed to inhibitors of mitochondrial functions has revealed irreversible deletorious eff ect upon energetic potential of these cells. Erythropoietin (EPO) does not reverse the DNP-induced damage, but partially restores mitochondrial damage induced by DCDD, a specifi c inhibitor of the F0F1 mitochondrial membrane ATP-ase.
3. More extended studies are required, in order to screen positive eff ects of EPO in other non-erythroid cell types.
Conflict of interests
No potential confl icts of interests are reported.
References
1. Jelkmann W., Gross A.J.(Eds.). Erythropoietin, Springer-Verlag Berlin Yeidelberg New York, 1989,180 p.
2. Biggar P, Kim GH. Treatment of renal anemia: Erythropoiesis stimulating agents and beyond. Kidney Res Clin Pract. 2017; 36(3):209-223.
3. Osikov M.V., Simonyan E.V., Saedgalina O.T., Fedosov A.A. Mechanisms of erythropoietin infl uence on the quantitative composition of blood lymphocytes in experimental thermal injury. Modern Problems of Science and Education. 2016 (2). URL: https://elibrary.ru/download/elibrary_25869790_84106576.pdf. (In Russian).
4. Lifshitz L., Avneon M., Prutchi-Sagiv S., Katz O.,- Gassmann M., Mittelman M.,Neuman. Immunomodulatory functions of erythropoietin. Focus uni-luebeck. 8th Luebeck Conference «Pathophysiology and Pharmacology of Erythropoietin and other Hemopoietic Growth Factors».Suppl. 2009, P. 28.
5. Todosenko NM, Shmarov VA, Malashchenko VV, Meniailo ME, Melashchenko OB, Gazatova ND, Goncharov AG, Seledtsov VI. Erythropoietin exerts direct immunomodulatory eff ects on the cytokine production by activated human T-lymphocytes. Int Immunopharmacol. 2016; 36:277-281.
6. Wang S, Zhang C, Li J, Niyazi S, Zheng L, Xu M, Rong R, Yang C, Zhu T. Erythropoietin protects against rhabdomyolysis- induced acute kidney injury by modulating macrophage polarization. Cell Death Dis. 2017; 8(4):e2725.
7. Lisowska KA, Bryl E, Witkowski JM. Erythropoietin receptor is detectable on peripheral blood lymphocytes and its expression increases in activated T lymphocytes. Haematologica. 2011;96(3):e12-3
8. Hisatomi K, Nakao M, Isomura T, Kosuga K, Itoh K. Effect of recombinant erythropoietin on peripheral T lymphocytes. J Th orac Cardiovasc Surg. 1995 109(4):809.
9. Morozova G.I., Parkhomenko T.V., Klitsenko O.A., Tomson V.V. Stimulating eff ect of erythropoietin on thymocyte energetics established in vitro with a potential-sensitive fl uorescent probe in the mitochondria. Biochem. Suppl. Series A: Membr Cell Biology. 2007; 1 (4):325-330.
10. Parkhomenko T.V., Morozova G.I., Klytsenko O.A., Tomson V.V. Quantitative evaluationof erythropoietin (EPO) infl uence on rat T-lymphocytes. Annals of Hematology. 2000; 79 (5): B8.
11. Futai M., Noumi T., Maeda M. ATP – synthase (H+-ATP- ASE) – results by combined biochemical and molecular biological approaches. Annual Review of Biochemistry. 1989; 58:111-136.
12. Clejan L., Bosch C.G., Beattie D.S. Inhibition by dicyclohexylcarbodiimide of proton ejection but not electron-transfer in rat-liver mitochondria. Journal of Biological Chemistry. 1984; 259 (21):13017-13020.
13. Lisowska KA, Dębska-Ślizień A, Jasiulewicz A, Jóźwik A, Rutkowski B, Bryl E, Witkowski JM. Flow cytometric analysis of STAT5 phosphorylation and CD95 expression in CD4+ T lymphocytes treated with recombinant human erythropoietin. J Recept Signal Transduct Res. 2011; 31(3):241-246.
Introduction
Erythropoietin (EPO) was initially known as a physiological growth factor which is produced, mainly, by renal glomeruli, macrophages and some other cell types. EPO is shown to support survival and mitotic activity, as well as inhibit apoptosis of late erythroid precursor cells in bone marrow [1]. Th erefore, recombinant erythropoietins-alpha (Eprex, Epobioicrine, Epostim etc.) are widely used to correct anemias in diff erent diseases and posttransplant conditions [2].
However, biological mechanisms of EPO action upon immune cells are still not clear. E.g., antioxidant in vivo eff ects of EPO (reduced lipid peroxidation in blood lymphocytes) are shown by Osikov et al. [3]. Immunotropic eff ects of EPO are recently studied, due to its immunomodulatory eff ects under clinical and experimental conditions [4-6]. Response of lymphocytes and macrophages to EPO seems to be mediated by the EPO receptors on their surface [7]. In vitro biological eff ects of EPO towards T-lymphoid cells were previously shown by Hisatomi et al. [8] who demonstrated suppression of IL-2 gene expression in TLC cells after their short-term (6 h) incubation with EPO. Hence, EPO is able to exert fast immediate action upon T-lymphoid cells over short incubation terms. Indeed, we have also revealed modulatory effect of EPO upon rat thymocytes using a specifi c potential-sensitive chemical probe [9]. EPO was found to exert activating eff ect upon the TLC by changing total transmembrane potential of plasmatic (Δφp) and mitochondrial membranes (Δφm). This activation correlated with increased numbers of the probe-labeled fl uorescent mitochondria in exposed cells [10]. To discern these mechanisms, we used specifi c inhibitors of oxydative phosphorylation, in order to assess the type of potential responsible for these EPO eff ects. Hence, the aim of this work was to evaluate the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes in order to specify this response to EPO, either Δφm, or Δφp. To address this issue, we used specifi c inhbitors of phosphorylation in the respiratory chain which serve as important tools for studying energy supply in the living cells.
To address this issue, we used specifi c inhibitors of oxydative phosphorylation. In order to evaluate the role of mitochondrial functions for energy supply in thymic lymphocytes exposed to EPO. Hence, the aim of this study was to assess a restoring EPO eff ect upon the in vitro response of thymocytes aft er treatment with diff erent specifi c inhibitors of oxidative phosphorylation.
Materials and Methods
We have studied lymphoid cells isolated from thymuses of white Wistar rats (200-300 g), aft er gentle mincing of thymus glands [9]. Th e cells were resuspended in standard Hank’s solution at 2 to 3x107 cells/mL. Percentage of viable (dye-excluding) cells was determined by routine Trypan Blue staining.
To determine possible points for EPO actions, we used different inhibitors of the oxidative phosphorylation, i.e., dinitrophenol (DNP, Sigma, USA), an inhibitor of respiratory chain and uncoupler of oxidative phosphorylation; pentachlorophenol (PCP, Sigma USA), an uncoupler of oxidative phosphorylation; dicyclohexyl carbodiimide (DCCD, Sigma, USA), an inhibitor of mitochondrial membrane-bound ATP-ase domain. Erythropoietin (EPO) was purchased from Cilag (Eprex) was dissolved in Hank’s solution. A potential- sensitive fl uorescent probe [4-(p-dimethylaminostyryl)- 1-methylpyridinium] (DSM) was used to test the energy potential of cells. DSM was produced and purchased from the Latvian Institute of Organic Synthesis [9]. Th e thymocyte suspensions in Eppendorf-type tubes were pre-incubated with inhibitors for 10…20…40 min at 37°С, then EPO was added at the fi nal concentration of 2U/ml), followed by incubation for 30 min, addition of the DSM probe (1.5 μM), and post-incubated for 20 min. Final concentrations of inhibitors were as follows: DNP, 0.1 mM; PCP, 1.5 μM; DCCD, 0.1 mM, at a v/v ratio of <5% to the initial suspension volume. The control samples of cells were supplied with equal volumes of Hanks’ solution, and, aft er 10…30 min. at 37°С, were incubated with DSM and EPO, as described above. Control and experimental TLC samples were then studied at the luminescent microscope LUMAM – R8 (LOMO, St. Petersburg, Russia) at a 900x magnifi cation, using a temperature-controlled stage for the count chamber. Th e fl uorescence was excited by a mercury lamp (λ= 405-436 nm). To measure light emission, a FMEL-1 photometric device was used, with an interference fi lter with a maximum transmission at 585 nm. Fluorescence intensity was manually measured for single cells localized in the vision fi eld, then transformed to a digital signal. Th e numbers of DSM-stained bright mitochondria, looking as intracellular yellow granules, were counted per each single cell (the nm/c values) [9]. Fift y to seventy cells were studied per sample, and the mean fl uorescence intensity was calculated as conventional units (F̃, arbitrary units). The fluorescent signal did not quench over the measurement time. Photomicrographs of the DSM-stained cells were performed with a TSA 5.0 camera mounted in the LOMO R8 microscope, and analyzed by a Microanalysis View soft ware (from the same manufacturer). Statistical evaluation of the data was performed by the Spearmen range correlation criterion. A total of 8,000 cells have been studied in 160 samples. Each independent experiment included 3 to 5 measure points.
Results
Initial amount of intact thymic lymphoid cells in cell suspensions was 92 to 96%. Several control experiments with have shown a decrease of nm/c and F̃ values for these cells aft er incubation with either inhibitor. Th e degree of such decrease depended on the type of inhibiting substance, and incubation terms (Table 1, Fig. 1 A, B, C). Th e most pronounced and faster eff ect was observed with DNP, i.e., fl uorescent mitochondria became virtually absent in DNP-treated cells as soon as aft er 10 min of exposure. F̃ values were also decreased by 20 min, with both nm/c and F̃ reduction. Fluorescent mitochondria disappeared by 40 min, with F̃ at the background levels. EPO addition did not restore F̃ and nm/c- parameters. Th e dynamics of thymocytes with absent mitochondrial fl uorescence aft er DNP exposure shown in Fig. 1A (NC-EM,%), like as absence of recovery aft er EPO addition. Th is eff ect may be caused by classical protonophore properties of DNP which irreversibly reduces both mentioned components of electrochemical gradient, thus causing the mitochondrial membrane depolarization.
Table 1. Time-dependent changes of mean fluorescence (F, arb. units) and number of fluorescent mitochondria per one cell (nm/c) upon short-term exposure of rat TLC to respiratory chain inhibitors followed by EPO treatment
Note: * – P< 0.01; ** – P< 0.025; nm/c – mean number of fl uorescent mitochondria per cell; F̃, arb. units – mean fl uorescence levels for all the cell measured at the given time points. Controls: TLC incubated without inhibitors at 37°С, with EPO supplied aft er 40 min. of incubation. Experimental samples: cells with addition of DNP, or PCP, or DCCD followed by incubation with EPO at 37°С. Mean values (M) and mean error (m) are shown for each time point
Similar, but less pronounced decrease was observed 10 min aft er treatment with PCP, i.e., n m/c dropped by 37%, and F̃, by ~ 35%. Following 20-min incubation, we observed only ~ 26% nm/c and ~ 25% F̃ of control values. At 40 min., no fl uorescent mitochondria are seen.
Meanwhile, Fig. 1B shows increase of non-fl uorescent cell numbers (NC-EM, %) induced by PCP, followed by a recovery induced by EPO supplement. The inhibitory effect of PCP upon thymocytes proved to be partially reversible aft er addition of EPO (nm/c recovery by ~23%, and F̃ values by ~20%).
A 10-min. incubation of thymocytes with DCCD again retains only a part of fl uorescent cells (nm/c, 30%, and ~33% F̃). Only 18% nm/c and ~ 20% F̃ remain aft er 20 min. with DCCD, a mitochondrial membrane-bound ATP-ase. At 40 min. with DCDD, no fl uorescence was observed in the cells, with background F̃ values. However, 30-min. incubation with EPO has resulted into recovery of mitochondria-associated fl uorescence to 42% for nm/c and 38% for F̃ levels, as compared with control samples. Fig. 1C illustrates the dynamics (NC-EM, %) of de-energized thymocytes induced by DCCD followed by restoration of potential-coupled fl uorescence aft er EPO treatment.
Typical patterns of DSM-stained cells before and aft er treatment with mitochondrial ATP-ase inhibitor (DCCD) are shown in Fig. 2 A-C.
Figure 1. Changing amounts of rat thymic lymphocytes devoid of fluorescent mitochondria (NC-EM, %) from initial
time points (0 min.), following incubation with different inhibitors, and after EPO addition. Incubation at 37°C with
DNP (Fig. 1A); PCP (Fig. 1B); DCCD (Fig. 1C) was followed by uniform exposure to EPO. Abscissa: incubation terms (min);
ordinate, mean values of TLC without fluorescent mitochondria (NC-EM, %) for each time point. Vertical bars show
appropriate confidence intervals for P<0.05 as compared to initial values
Figure 2. Rat thymocytes stained with a fluorescent DSM probe. 2A, an original sample after incubation with EPO,
F=52,0 arb. units; 2B, cells after 40 min of incubation with DCCD, F=3,0 arb. units; 2C, thymocytes after exposure of
DCCD-treated cells to EPO, F=20,0 arb. units
Discussion
In our works, we have used inhibitor analysis, in order to assess the mechanisms which regulate anti-apoptotic eff ects of erythropoietin. Th e transmembrane potential of membranes in thymocytes was determined as fl uorescence intensity of DSM probe. Total DSM fl uorescence depends on a summary potentials of plasmatic and mitochondrial membranes. Earlier we have found that EPO acts upon thymic lymphoid cells by changing electric charge of cellular membranes. Th e EPO stimulatory eff ect is accompanied by increased nm/c, due to proton potential (Δφm), and/or external membrane potential (Δφp) [9].
Our data suggest that some metabolic eff ects of EPO are exerted via mitochondrial respiratory pathways. EPO was shown to reverse the de-energizing eff ects of DCCD, thus presuming functional changes of F0F1 membrane ATP which is specifi cally inhibited by the DCCD.
The mitochondrial F0F1-ATP-ase is a complex lipoprotein containing of hydrophilic catalytic center (F1), and a membrane domain (F0) [11]. DCDD used in this work is a specific proton translocation inhibitor in the F0F1 ATP-ase [12], causing decrease in nm/c and general F̃ shown in our experiments, thus refl ecting a critical role of ATP-ase for sustaining the mitochondrial membrane potential. Th e reduced fl uorescence of DSM-induced mitochondria could be considered as mitochondrial de-energization, which proved to be reversible by EPO treatment. Th is fi nding may refl ect ability of EPO to restore functional integrity of mitochondrial membranes as a component of their eff ects upon immune system. The restored mitochondrial functions in the target cells for EPO allow to perform regulatory signaling in lymphoid cells, e.g., via phosphorylation of some transcription factors, e.g., STAT5 in lymphoid cells and tissues [13]. Further studies in other lymphoid cell models could further elucidate the role of EPO as a regulator of mitochondrial function.
Conclusions
1. Thymocytes may represent a non-usual, but suitable model for evaluation of growth factor eff ects upon dividing, apoptosis- prone immune cells.
2. The in vitro testing of modifying EPO eff ects in thymocytes exposed to inhibitors of mitochondrial functions has revealed irreversible deletorious eff ect upon energetic potential of these cells. Erythropoietin (EPO) does not reverse the DNP-induced damage, but partially restores mitochondrial damage induced by DCDD, a specifi c inhibitor of the F0F1 mitochondrial membrane ATP-ase.
3. More extended studies are required, in order to screen positive eff ects of EPO in other non-erythroid cell types.
Conflict of interests
No potential confl icts of interests are reported.
References
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2. Biggar P, Kim GH. Treatment of renal anemia: Erythropoiesis stimulating agents and beyond. Kidney Res Clin Pract. 2017; 36(3):209-223.
3. Osikov M.V., Simonyan E.V., Saedgalina O.T., Fedosov A.A. Mechanisms of erythropoietin infl uence on the quantitative composition of blood lymphocytes in experimental thermal injury. Modern Problems of Science and Education. 2016 (2). URL: https://elibrary.ru/download/elibrary_25869790_84106576.pdf. (In Russian).
4. Lifshitz L., Avneon M., Prutchi-Sagiv S., Katz O.,- Gassmann M., Mittelman M.,Neuman. Immunomodulatory functions of erythropoietin. Focus uni-luebeck. 8th Luebeck Conference «Pathophysiology and Pharmacology of Erythropoietin and other Hemopoietic Growth Factors».Suppl. 2009, P. 28.
5. Todosenko NM, Shmarov VA, Malashchenko VV, Meniailo ME, Melashchenko OB, Gazatova ND, Goncharov AG, Seledtsov VI. Erythropoietin exerts direct immunomodulatory eff ects on the cytokine production by activated human T-lymphocytes. Int Immunopharmacol. 2016; 36:277-281.
6. Wang S, Zhang C, Li J, Niyazi S, Zheng L, Xu M, Rong R, Yang C, Zhu T. Erythropoietin protects against rhabdomyolysis- induced acute kidney injury by modulating macrophage polarization. Cell Death Dis. 2017; 8(4):e2725.
7. Lisowska KA, Bryl E, Witkowski JM. Erythropoietin receptor is detectable on peripheral blood lymphocytes and its expression increases in activated T lymphocytes. Haematologica. 2011;96(3):e12-3
8. Hisatomi K, Nakao M, Isomura T, Kosuga K, Itoh K. Effect of recombinant erythropoietin on peripheral T lymphocytes. J Th orac Cardiovasc Surg. 1995 109(4):809.
9. Morozova G.I., Parkhomenko T.V., Klitsenko O.A., Tomson V.V. Stimulating eff ect of erythropoietin on thymocyte energetics established in vitro with a potential-sensitive fl uorescent probe in the mitochondria. Biochem. Suppl. Series A: Membr Cell Biology. 2007; 1 (4):325-330.
10. Parkhomenko T.V., Morozova G.I., Klytsenko O.A., Tomson V.V. Quantitative evaluationof erythropoietin (EPO) infl uence on rat T-lymphocytes. Annals of Hematology. 2000; 79 (5): B8.
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13. Lisowska KA, Dębska-Ślizień A, Jasiulewicz A, Jóźwik A, Rutkowski B, Bryl E, Witkowski JM. Flow cytometric analysis of STAT5 phosphorylation and CD95 expression in CD4+ T lymphocytes treated with recombinant human erythropoietin. J Recept Signal Transduct Res. 2011; 31(3):241-246.
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Эритропоэтин (ЭПО) является физиологическим стимулятором эритропоэза. Одним из основных эффектов ЭПО является снижение частоты апоптоза эритроидных клеток-предшественниц в костном мозге. Эти свойства ЭПО широко применяются при лечении различных заболеваний системы крови, в том числе – после трансплантации стволовых клеток. Ранее было установлено, что ЭПО оказывает активирующее воздействие на Т-лимфоциты (ТЛЦ), сопровождающееся увеличением количества флуоресцирующих митохондрий в клетке (nm/c) и увеличением суммарного трансмембранного потенциала на плазматической (Δφp) и митохондриальных мембранах (Δφm). Однако остается неясным, какой именно мембранный потенциал реагирует на воздействие ЭПО: Δφm, или (и) Δφp. Для ответа на этот вопрос мы использовали специфические ингибиторы окислительного фосфорилирования. Цель настоящего исследования – оценка роли митохондриальных функций в воздействии ЭПО на лимфоциты тимуса.
Материалы и методы
Исследовалось влияние ЭПО (“Eprex”, Cilag) на флуоресценцию ТЛЦ крыс in vitro после краткосрочной инкубации и воздействия несколькими ингибиторами: динитрофенолом (ДНФ) – ингибитором дыхательной цепи и разобщителем окислительного фосфорилирования; пентахлорфенолом (ПХФ) – разобщителем окислительного фосфорилирования; дициклогексилкарбодиимидом (ДЦКД) – ингибитором мембрансвязанной части АТФ-азы митохондриальной мембраны с помощью зонда DSM [4-(p-диметиламиностирилил)-1-метил пиридиний], определяющего трансмембранный градиент электрического поля. ТЛЦ выделяли из тимусов по стандартной методике. Окрашенные ДСМ клетки исследовали на люминесцентном микроскопе («Люмам – Р 8», ЛОМО, Россия) с использованием термостатированного столика. В каждом препарате измеряли флуоресценцию 50-70 клеток и рассчитывали среднюю интенсивность флуоресценции ТЛЦ (F̃). В каждой флуоресцирующей клетке подсчитывали nm/c. Статистическую обработку данных экспериментов проводили по коэффициенту корреляции рангов Спирмена.
Результаты и обсуждение
В серии экспериментов с ТЛЦ зарегистрировано снижение nm/c и F̃ после инкубации со всеми использованными ингибиторами, причем степень и скорость снижения этих параметров зависела от типа ингибитора и длительности инкубации. Максимальное снижение энергетики ТЛЦ достигалось при инкубации с ДНФ, после которого ЭПО не восстанавливает F̃ и nm/c. После инкубации с ПХФ ЭПО восстанавливает ~20-23% nm/c и F̃. Реакция ТЛЦ на ДЦКД подтверждает важную роль АТФ-азы в поддержании мембранного митохондриального потенциала. После деэнергизации ТЛЦ под действием ДЦКД, ЭПО восстанавливает ~42% nm/c и ~38% F̃.
Заключение
ЭПО способен частично восстанавливать поляризацию мембран митохондрий в ТЛЦ, нарушенную в результате воздействия ингибитора АТФ-азы (ДЦКД).
Ключевые слова
Эритропоэтин, Т-лимфоциты, энергетическая активность, ингибиторы, потенциалчувствительный витальный флуоресцентный зонд-катион 4-(п-диметиламиностирил)-1-метилпиридиния (ДСМ).
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One of the main eff ects of EPO is to prevent apoptosis of erythroid progenitor cells in the bone marrow. Th ese properties of EPO are widely used for treatment of various hematopoietic disorders including posttransplant conditions. Previously, it was found that activating EPO-eff ect on T-lymphocytes (TLC) accompanied by an increase in the number of fluorescent mitochondria (n m/c) and an increase in the total transmembrane potential on plasmatic (Δφp) and mitochondrial membranes (Δφm). However, it remains unclear which membrane potential is responsible for the EPO effect. Hence, we used specifi c inhibitors of oxidative phosphorylation in the respiratory chain. The aim of the present work was to assess the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes. </p> <p style="text-align: justify;"> <span style="font-family: Cuprum, sans-serif; font-size: 26px;">Materials and methods</span> </p> <p style="text-align: justify;"> We studied EPO (Eprex, Cilag) infl uence on fl uorescence of rat TLC aft er short-term incubation and treatment with some inhibitors: dinitrophenol (DNP-uncoupler of oxidative phosphorylation and inhibitor of respiratory chain), pentachlorphenol (PCP- uncoupler of oxidative phosphorylation), N,N -dicyclohexylcarbodiimide (DCCD- inhibitor of Ca2+- dependent mitochondria ATP-аse). Th e cells were then tested by electrical fi eld gradient sensitive probe DSM [4-(p-dimethylaminostyryl)- 1-methylpyridinium]. Rat TLC were isolated according to the standard method. Th e microfl uorimetric studies of DSM-stained TLC were performed by means of fl uorescent microscope “Lumam R-8”, “LOMO”, Russia) with thermostatic plate. Fift y to 70 single cells were measured per each specimen the mean fl uorescence intensity of TLC was calculated (F̃), as well as nm/c values. Statistical evaluation of the data was performed by the Spearmen range correlation. </p> <h2 style="text-align: justify;">Results</h2> <p style="text-align: justify;"> In a series of experiments with TLC, we have registered a decrease in F̃ and nm/c aft er incubation with all used inhibitors. It was found that the diff erence in decrease of nm/c rates and F̃ values depends on the type of inhibitor and on the duration of incubation. Maximal irreversible reduction of the TLC energy potential (F̃ and nm/c) after incubation was seen with DNP being not restored by EPO. Aft er incubation with PCP, EPO restores nm/c and F̃ by ca. 20-23%. Th e reaction of TLC on the DCCD confirms the important role of the ATP-ase for maintenance of mitochondrial membrane potential. After de-energization of TLC by DCCD, EPO has the maximum rescuing effect, i.e. recovery by approx. 42% for nm/c and ~38%<br> for F̃ values. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> EPO is able to partially recover the damage and polarization of the mitochondria membranes in TLC disturbed aft er exposure to specifi c ATP-ase inhibitor (DCCD). This in vitro approach may be used for screening other growth factors. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Erythropoietin, T-lymphocytes, energy activity, inhibitors, electrical field gradient sensitive probe DSM [4-(p-dimethylaminostyryl)-1-methylpyridinium]. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3458) "Erythropoietin (EPO) is a physiological stimulator of erythropoiesis. One of the main eff ects of EPO is to prevent apoptosis of erythroid progenitor cells in the bone marrow. Th ese properties of EPO are widely used for treatment of various hematopoietic disorders including posttransplant conditions. Previously, it was found that activating EPO-eff ect on T-lymphocytes (TLC) accompanied by an increase in the number of fluorescent mitochondria (n m/c) and an increase in the total transmembrane potential on plasmatic (Δφp) and mitochondrial membranes (Δφm). However, it remains unclear which membrane potential is responsible for the EPO effect. Hence, we used specifi c inhibitors of oxidative phosphorylation in the respiratory chain. The aim of the present work was to assess the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes.
Materials and methods
We studied EPO (Eprex, Cilag) infl uence on fl uorescence of rat TLC aft er short-term incubation and treatment with some inhibitors: dinitrophenol (DNP-uncoupler of oxidative phosphorylation and inhibitor of respiratory chain), pentachlorphenol (PCP- uncoupler of oxidative phosphorylation), N,N -dicyclohexylcarbodiimide (DCCD- inhibitor of Ca2+- dependent mitochondria ATP-аse). Th e cells were then tested by electrical fi eld gradient sensitive probe DSM [4-(p-dimethylaminostyryl)- 1-methylpyridinium]. Rat TLC were isolated according to the standard method. Th e microfl uorimetric studies of DSM-stained TLC were performed by means of fl uorescent microscope “Lumam R-8”, “LOMO”, Russia) with thermostatic plate. Fift y to 70 single cells were measured per each specimen the mean fl uorescence intensity of TLC was calculated (F̃), as well as nm/c values. Statistical evaluation of the data was performed by the Spearmen range correlation.
Results
In a series of experiments with TLC, we have registered a decrease in F̃ and nm/c aft er incubation with all used inhibitors. It was found that the diff erence in decrease of nm/c rates and F̃ values depends on the type of inhibitor and on the duration of incubation. Maximal irreversible reduction of the TLC energy potential (F̃ and nm/c) after incubation was seen with DNP being not restored by EPO. Aft er incubation with PCP, EPO restores nm/c and F̃ by ca. 20-23%. Th e reaction of TLC on the DCCD confirms the important role of the ATP-ase for maintenance of mitochondrial membrane potential. After de-energization of TLC by DCCD, EPO has the maximum rescuing effect, i.e. recovery by approx. 42% for nm/c and ~38%
for F̃ values.
Conclusion
EPO is able to partially recover the damage and polarization of the mitochondria membranes in TLC disturbed aft er exposure to specifi c ATP-ase inhibitor (DCCD). This in vitro approach may be used for screening other growth factors.
Keywords
Erythropoietin, T-lymphocytes, energy activity, inhibitors, electrical field gradient sensitive probe DSM [4-(p-dimethylaminostyryl)-1-methylpyridinium].
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One of the main eff ects of EPO is to prevent apoptosis of erythroid progenitor cells in the bone marrow. Th ese properties of EPO are widely used for treatment of various hematopoietic disorders including posttransplant conditions. Previously, it was found that activating EPO-eff ect on T-lymphocytes (TLC) accompanied by an increase in the number of fluorescent mitochondria (n m/c) and an increase in the total transmembrane potential on plasmatic (Δφp) and mitochondrial membranes (Δφm). However, it remains unclear which membrane potential is responsible for the EPO effect. Hence, we used specifi c inhibitors of oxidative phosphorylation in the respiratory chain. The aim of the present work was to assess the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes. </p> <p style="text-align: justify;"> <span style="font-family: Cuprum, sans-serif; font-size: 26px;">Materials and methods</span> </p> <p style="text-align: justify;"> We studied EPO (Eprex, Cilag) infl uence on fl uorescence of rat TLC aft er short-term incubation and treatment with some inhibitors: dinitrophenol (DNP-uncoupler of oxidative phosphorylation and inhibitor of respiratory chain), pentachlorphenol (PCP- uncoupler of oxidative phosphorylation), N,N -dicyclohexylcarbodiimide (DCCD- inhibitor of Ca2+- dependent mitochondria ATP-аse). Th e cells were then tested by electrical fi eld gradient sensitive probe DSM [4-(p-dimethylaminostyryl)- 1-methylpyridinium]. Rat TLC were isolated according to the standard method. Th e microfl uorimetric studies of DSM-stained TLC were performed by means of fl uorescent microscope “Lumam R-8”, “LOMO”, Russia) with thermostatic plate. Fift y to 70 single cells were measured per each specimen the mean fl uorescence intensity of TLC was calculated (F̃), as well as nm/c values. Statistical evaluation of the data was performed by the Spearmen range correlation. </p> <h2 style="text-align: justify;">Results</h2> <p style="text-align: justify;"> In a series of experiments with TLC, we have registered a decrease in F̃ and nm/c aft er incubation with all used inhibitors. It was found that the diff erence in decrease of nm/c rates and F̃ values depends on the type of inhibitor and on the duration of incubation. Maximal irreversible reduction of the TLC energy potential (F̃ and nm/c) after incubation was seen with DNP being not restored by EPO. Aft er incubation with PCP, EPO restores nm/c and F̃ by ca. 20-23%. Th e reaction of TLC on the DCCD confirms the important role of the ATP-ase for maintenance of mitochondrial membrane potential. After de-energization of TLC by DCCD, EPO has the maximum rescuing effect, i.e. recovery by approx. 42% for nm/c and ~38%<br> for F̃ values. </p> <h2 style="text-align: justify;">Conclusion</h2> <p style="text-align: justify;"> EPO is able to partially recover the damage and polarization of the mitochondria membranes in TLC disturbed aft er exposure to specifi c ATP-ase inhibitor (DCCD). This in vitro approach may be used for screening other growth factors. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Erythropoietin, T-lymphocytes, energy activity, inhibitors, electrical field gradient sensitive probe DSM [4-(p-dimethylaminostyryl)-1-methylpyridinium]. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3458) "Erythropoietin (EPO) is a physiological stimulator of erythropoiesis. One of the main eff ects of EPO is to prevent apoptosis of erythroid progenitor cells in the bone marrow. Th ese properties of EPO are widely used for treatment of various hematopoietic disorders including posttransplant conditions. Previously, it was found that activating EPO-eff ect on T-lymphocytes (TLC) accompanied by an increase in the number of fluorescent mitochondria (n m/c) and an increase in the total transmembrane potential on plasmatic (Δφp) and mitochondrial membranes (Δφm). However, it remains unclear which membrane potential is responsible for the EPO effect. Hence, we used specifi c inhibitors of oxidative phosphorylation in the respiratory chain. The aim of the present work was to assess the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes.
Materials and methods
We studied EPO (Eprex, Cilag) infl uence on fl uorescence of rat TLC aft er short-term incubation and treatment with some inhibitors: dinitrophenol (DNP-uncoupler of oxidative phosphorylation and inhibitor of respiratory chain), pentachlorphenol (PCP- uncoupler of oxidative phosphorylation), N,N -dicyclohexylcarbodiimide (DCCD- inhibitor of Ca2+- dependent mitochondria ATP-аse). Th e cells were then tested by electrical fi eld gradient sensitive probe DSM [4-(p-dimethylaminostyryl)- 1-methylpyridinium]. Rat TLC were isolated according to the standard method. Th e microfl uorimetric studies of DSM-stained TLC were performed by means of fl uorescent microscope “Lumam R-8”, “LOMO”, Russia) with thermostatic plate. Fift y to 70 single cells were measured per each specimen the mean fl uorescence intensity of TLC was calculated (F̃), as well as nm/c values. Statistical evaluation of the data was performed by the Spearmen range correlation.
Results
In a series of experiments with TLC, we have registered a decrease in F̃ and nm/c aft er incubation with all used inhibitors. It was found that the diff erence in decrease of nm/c rates and F̃ values depends on the type of inhibitor and on the duration of incubation. Maximal irreversible reduction of the TLC energy potential (F̃ and nm/c) after incubation was seen with DNP being not restored by EPO. Aft er incubation with PCP, EPO restores nm/c and F̃ by ca. 20-23%. Th e reaction of TLC on the DCCD confirms the important role of the ATP-ase for maintenance of mitochondrial membrane potential. After de-energization of TLC by DCCD, EPO has the maximum rescuing effect, i.e. recovery by approx. 42% for nm/c and ~38%
for F̃ values.
Conclusion
EPO is able to partially recover the damage and polarization of the mitochondria membranes in TLC disturbed aft er exposure to specifi c ATP-ase inhibitor (DCCD). This in vitro approach may be used for screening other growth factors.
Keywords
Erythropoietin, T-lymphocytes, energy activity, inhibitors, electrical field gradient sensitive probe DSM [4-(p-dimethylaminostyryl)-1-methylpyridinium].
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3458) "Erythropoietin (EPO) is a physiological stimulator of erythropoiesis. One of the main eff ects of EPO is to prevent apoptosis of erythroid progenitor cells in the bone marrow. Th ese properties of EPO are widely used for treatment of various hematopoietic disorders including posttransplant conditions. Previously, it was found that activating EPO-eff ect on T-lymphocytes (TLC) accompanied by an increase in the number of fluorescent mitochondria (n m/c) and an increase in the total transmembrane potential on plasmatic (Δφp) and mitochondrial membranes (Δφm). However, it remains unclear which membrane potential is responsible for the EPO effect. Hence, we used specifi c inhibitors of oxidative phosphorylation in the respiratory chain. The aim of the present work was to assess the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes.
Materials and methods
We studied EPO (Eprex, Cilag) infl uence on fl uorescence of rat TLC aft er short-term incubation and treatment with some inhibitors: dinitrophenol (DNP-uncoupler of oxidative phosphorylation and inhibitor of respiratory chain), pentachlorphenol (PCP- uncoupler of oxidative phosphorylation), N,N -dicyclohexylcarbodiimide (DCCD- inhibitor of Ca2+- dependent mitochondria ATP-аse). Th e cells were then tested by electrical fi eld gradient sensitive probe DSM [4-(p-dimethylaminostyryl)- 1-methylpyridinium]. Rat TLC were isolated according to the standard method. Th e microfl uorimetric studies of DSM-stained TLC were performed by means of fl uorescent microscope “Lumam R-8”, “LOMO”, Russia) with thermostatic plate. Fift y to 70 single cells were measured per each specimen the mean fl uorescence intensity of TLC was calculated (F̃), as well as nm/c values. Statistical evaluation of the data was performed by the Spearmen range correlation.
Results
In a series of experiments with TLC, we have registered a decrease in F̃ and nm/c aft er incubation with all used inhibitors. It was found that the diff erence in decrease of nm/c rates and F̃ values depends on the type of inhibitor and on the duration of incubation. Maximal irreversible reduction of the TLC energy potential (F̃ and nm/c) after incubation was seen with DNP being not restored by EPO. Aft er incubation with PCP, EPO restores nm/c and F̃ by ca. 20-23%. Th e reaction of TLC on the DCCD confirms the important role of the ATP-ase for maintenance of mitochondrial membrane potential. After de-energization of TLC by DCCD, EPO has the maximum rescuing effect, i.e. recovery by approx. 42% for nm/c and ~38%
for F̃ values.
Conclusion
EPO is able to partially recover the damage and polarization of the mitochondria membranes in TLC disturbed aft er exposure to specifi c ATP-ase inhibitor (DCCD). This in vitro approach may be used for screening other growth factors.
Keywords
Erythropoietin, T-lymphocytes, energy activity, inhibitors, electrical field gradient sensitive probe DSM [4-(p-dimethylaminostyryl)-1-methylpyridinium].
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Пархоменко, Владимир В. Томсон, Олег В. Галибин" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(103) "Татьяна В. Пархоменко, Владимир В. Томсон, Олег В. Галибин" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(103) "Татьяна В. Пархоменко, Владимир В. Томсон, Олег В. Галибин" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20926" ["VALUE"]=> array(2) { ["TEXT"]=> string(5899) "<p style="text-align: justify;"> Эритропоэтин (ЭПО) является физиологическим стимулятором эритропоэза. Одним из основных эффектов ЭПО является снижение частоты апоптоза эритроидных клеток-предшественниц в костном мозге. Эти свойства ЭПО широко применяются при лечении различных заболеваний системы крови, в том числе – после трансплантации стволовых клеток. Ранее было установлено, что ЭПО оказывает активирующее воздействие на Т-лимфоциты (ТЛЦ), сопровождающееся увеличением количества флуоресцирующих митохондрий в клетке (nm/c) и увеличением суммарного трансмембранного потенциала на плазматической (Δφp) и митохондриальных мембранах (Δφm). Однако остается неясным, какой именно мембранный потенциал реагирует на воздействие ЭПО: Δφm, или (и) Δφp. Для ответа на этот вопрос мы использовали специфические ингибиторы окислительного фосфорилирования. Цель настоящего исследования – оценка роли митохондриальных функций в воздействии ЭПО на лимфоциты тимуса. </p> <h2 style="text-align: justify;">Материалы и методы</h2> <p style="text-align: justify;"> Исследовалось влияние ЭПО (“Eprex”, Cilag) на флуоресценцию ТЛЦ крыс in vitro после краткосрочной инкубации и воздействия несколькими ингибиторами: динитрофенолом (ДНФ) – ингибитором дыхательной цепи и разобщителем окислительного фосфорилирования; пентахлорфенолом (ПХФ) – разобщителем окислительного фосфорилирования; дициклогексилкарбодиимидом (ДЦКД) – ингибитором мембрансвязанной части АТФ-азы митохондриальной мембраны с помощью зонда DSM [4-(p-диметиламиностирилил)-1-метил пиридиний], определяющего трансмембранный градиент электрического поля. ТЛЦ выделяли из тимусов по стандартной методике. Окрашенные ДСМ клетки исследовали на люминесцентном микроскопе («Люмам – Р 8», ЛОМО, Россия) с использованием термостатированного столика. В каждом препарате измеряли флуоресценцию 50-70 клеток и рассчитывали среднюю интенсивность флуоресценции ТЛЦ (F̃). В каждой флуоресцирующей клетке подсчитывали nm/c. Статистическую обработку данных экспериментов проводили по коэффициенту корреляции рангов Спирмена. </p> <h2 style="text-align: justify;">Результаты и обсуждение</h2> <p style="text-align: justify;"> В серии экспериментов с ТЛЦ зарегистрировано снижение nm/c и F̃ после инкубации со всеми использованными ингибиторами, причем степень и скорость снижения этих параметров зависела от типа ингибитора и длительности инкубации. Максимальное снижение энергетики ТЛЦ достигалось при инкубации с ДНФ, после которого ЭПО не восстанавливает F̃ и nm/c. После инкубации с ПХФ ЭПО восстанавливает ~20-23% nm/c и F̃. Реакция ТЛЦ на ДЦКД подтверждает важную роль АТФ-азы в поддержании мембранного митохондриального потенциала. После деэнергизации ТЛЦ под действием ДЦКД, ЭПО восстанавливает ~42% nm/c и ~38% F̃. </p> <h2 style="text-align: justify;">Заключение</h2> <p style="text-align: justify;"> ЭПО способен частично восстанавливать поляризацию мембран митохондрий в ТЛЦ, нарушенную в результате воздействия ингибитора АТФ-азы (ДЦКД). </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Эритропоэтин, Т-лимфоциты, энергетическая активность, ингибиторы, потенциалчувствительный витальный флуоресцентный зонд-катион 4-(п-диметиламиностирил)-1-метилпиридиния (ДСМ). </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5701) "Эритропоэтин (ЭПО) является физиологическим стимулятором эритропоэза. Одним из основных эффектов ЭПО является снижение частоты апоптоза эритроидных клеток-предшественниц в костном мозге. Эти свойства ЭПО широко применяются при лечении различных заболеваний системы крови, в том числе – после трансплантации стволовых клеток. Ранее было установлено, что ЭПО оказывает активирующее воздействие на Т-лимфоциты (ТЛЦ), сопровождающееся увеличением количества флуоресцирующих митохондрий в клетке (nm/c) и увеличением суммарного трансмембранного потенциала на плазматической (Δφp) и митохондриальных мембранах (Δφm). Однако остается неясным, какой именно мембранный потенциал реагирует на воздействие ЭПО: Δφm, или (и) Δφp. Для ответа на этот вопрос мы использовали специфические ингибиторы окислительного фосфорилирования. Цель настоящего исследования – оценка роли митохондриальных функций в воздействии ЭПО на лимфоциты тимуса.
Материалы и методы
Исследовалось влияние ЭПО (“Eprex”, Cilag) на флуоресценцию ТЛЦ крыс in vitro после краткосрочной инкубации и воздействия несколькими ингибиторами: динитрофенолом (ДНФ) – ингибитором дыхательной цепи и разобщителем окислительного фосфорилирования; пентахлорфенолом (ПХФ) – разобщителем окислительного фосфорилирования; дициклогексилкарбодиимидом (ДЦКД) – ингибитором мембрансвязанной части АТФ-азы митохондриальной мембраны с помощью зонда DSM [4-(p-диметиламиностирилил)-1-метил пиридиний], определяющего трансмембранный градиент электрического поля. ТЛЦ выделяли из тимусов по стандартной методике. Окрашенные ДСМ клетки исследовали на люминесцентном микроскопе («Люмам – Р 8», ЛОМО, Россия) с использованием термостатированного столика. В каждом препарате измеряли флуоресценцию 50-70 клеток и рассчитывали среднюю интенсивность флуоресценции ТЛЦ (F̃). В каждой флуоресцирующей клетке подсчитывали nm/c. Статистическую обработку данных экспериментов проводили по коэффициенту корреляции рангов Спирмена.
Результаты и обсуждение
В серии экспериментов с ТЛЦ зарегистрировано снижение nm/c и F̃ после инкубации со всеми использованными ингибиторами, причем степень и скорость снижения этих параметров зависела от типа ингибитора и длительности инкубации. Максимальное снижение энергетики ТЛЦ достигалось при инкубации с ДНФ, после которого ЭПО не восстанавливает F̃ и nm/c. После инкубации с ПХФ ЭПО восстанавливает ~20-23% nm/c и F̃. Реакция ТЛЦ на ДЦКД подтверждает важную роль АТФ-азы в поддержании мембранного митохондриального потенциала. После деэнергизации ТЛЦ под действием ДЦКД, ЭПО восстанавливает ~42% nm/c и ~38% F̃.
Заключение
ЭПО способен частично восстанавливать поляризацию мембран митохондрий в ТЛЦ, нарушенную в результате воздействия ингибитора АТФ-азы (ДЦКД).
Ключевые слова
Эритропоэтин, Т-лимфоциты, энергетическая активность, ингибиторы, потенциалчувствительный витальный флуоресцентный зонд-катион 4-(п-диметиламиностирил)-1-метилпиридиния (ДСМ).
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(5701) "Эритропоэтин (ЭПО) является физиологическим стимулятором эритропоэза. Одним из основных эффектов ЭПО является снижение частоты апоптоза эритроидных клеток-предшественниц в костном мозге. Эти свойства ЭПО широко применяются при лечении различных заболеваний системы крови, в том числе – после трансплантации стволовых клеток. Ранее было установлено, что ЭПО оказывает активирующее воздействие на Т-лимфоциты (ТЛЦ), сопровождающееся увеличением количества флуоресцирующих митохондрий в клетке (nm/c) и увеличением суммарного трансмембранного потенциала на плазматической (Δφp) и митохондриальных мембранах (Δφm). Однако остается неясным, какой именно мембранный потенциал реагирует на воздействие ЭПО: Δφm, или (и) Δφp. Для ответа на этот вопрос мы использовали специфические ингибиторы окислительного фосфорилирования. Цель настоящего исследования – оценка роли митохондриальных функций в воздействии ЭПО на лимфоциты тимуса.
Материалы и методы
Исследовалось влияние ЭПО (“Eprex”, Cilag) на флуоресценцию ТЛЦ крыс in vitro после краткосрочной инкубации и воздействия несколькими ингибиторами: динитрофенолом (ДНФ) – ингибитором дыхательной цепи и разобщителем окислительного фосфорилирования; пентахлорфенолом (ПХФ) – разобщителем окислительного фосфорилирования; дициклогексилкарбодиимидом (ДЦКД) – ингибитором мембрансвязанной части АТФ-азы митохондриальной мембраны с помощью зонда DSM [4-(p-диметиламиностирилил)-1-метил пиридиний], определяющего трансмембранный градиент электрического поля. ТЛЦ выделяли из тимусов по стандартной методике. Окрашенные ДСМ клетки исследовали на люминесцентном микроскопе («Люмам – Р 8», ЛОМО, Россия) с использованием термостатированного столика. В каждом препарате измеряли флуоресценцию 50-70 клеток и рассчитывали среднюю интенсивность флуоресценции ТЛЦ (F̃). В каждой флуоресцирующей клетке подсчитывали nm/c. Статистическую обработку данных экспериментов проводили по коэффициенту корреляции рангов Спирмена.
Результаты и обсуждение
В серии экспериментов с ТЛЦ зарегистрировано снижение nm/c и F̃ после инкубации со всеми использованными ингибиторами, причем степень и скорость снижения этих параметров зависела от типа ингибитора и длительности инкубации. Максимальное снижение энергетики ТЛЦ достигалось при инкубации с ДНФ, после которого ЭПО не восстанавливает F̃ и nm/c. После инкубации с ПХФ ЭПО восстанавливает ~20-23% nm/c и F̃. Реакция ТЛЦ на ДЦКД подтверждает важную роль АТФ-азы в поддержании мембранного митохондриального потенциала. После деэнергизации ТЛЦ под действием ДЦКД, ЭПО восстанавливает ~42% nm/c и ~38% F̃.
Заключение
ЭПО способен частично восстанавливать поляризацию мембран митохондрий в ТЛЦ, нарушенную в результате воздействия ингибитора АТФ-азы (ДЦКД).
Ключевые слова
Эритропоэтин, Т-лимфоциты, энергетическая активность, ингибиторы, потенциалчувствительный витальный флуоресцентный зонд-катион 4-(п-диметиламиностирил)-1-метилпиридиния (ДСМ).
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" } } } }
12/27/2018 04:01:00 pm
Afanasyev B. V. (St. Petersburg, Russia)
Wagemaker G. (Rotterdam, Netherlands)
Zander A. R. (Hamburg, Germany)
Fehse B. (Hamburg, Germany)
Chukhlovin A. B. (St. Petersburg, Russia)
Aleynikova O. V. (Minsk, Belarus)
Borset M. (Trondheim, Norway)
Chechetkin A. V. (St. Petersburg, Russia)
Fibbe W. (Leiden, Netherlands)
Galibin O. V. (St. Petersburg, Russia)
Hölzer D. (Frankfurt a.M., Germany)
Klimko N. N. (St. Petersburg, Russia)
Kolb H.-J. (München, Germany)
Kröger N. (Hamburg, Germany)
Kulagin A. D. (St. Petersburg, Russia)
Lange C. (Hamburg, Germany)
Mamaev N. N. (St. Petersburg, Russia)
Mikhailova N. B. (St. Petersburg, Russia)
Moiseev I. S. (St. Petersburg, Russia)
Nagler A. (Tel-Aviv, Israel)
Nemkov A. S. (St. Petersburg, Russia)
Paramonov I. V. (Kirov, Russia)
Roumiantsev A. G. (Moscow, Russia)
Savchenko V. G. (Moscow, Russia)
Smirnov A. V. (St. Petersburg, Russia)
Uss A. L. (Minsk, Belarus)
Zubarovskaya L. S. (St. Petersburg, Russia)
Editorial article
Review articles
`
Clinical studies
Clinical case
Experimental studies
1* Department of Preventive Stomatology
1** Biotechnology Department, R.Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation
1*** Laboratory of Pathomorphology, Th e University Research Center
1**** Laboratory of Invasive Technologies, Th e University Research Center
Editorial article
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Общий замысел и основание нашего журнала «Клеточная Терапия и Трансплантация» (КТТ) базировались на долгосрочном сотрудничестве российских и европейских специалистов в области трансплантации костного мозга (ТКМ). Совместные исследования в смежных научных областях основывались на предыдущих контактах между российскими и европейскими гематологами, онкологами и экспертами в области молекулярной биологии и генной терапии с 1990-х гг. Ввиду тесных международных рабочих связей между врачами и программ подготовки молодых российских специалистов в зарубежных клиниках, проф. Борис В. Афанасьев, проф. Дж. Вагемакер, проф. Аксель Р. Цандер и другие известные специалисты признали необходимость специального международного издания для лучшего сотрудничества в данной области. Генеральная концепция журнала «Клеточная Терапия и Трансплантация» была разработана в ходе дискуссий на встречах в Вильседе и Европейской группы ТКМ в 2006-2008 гг.<br>
Поэтому пилотный выпуск КТТ появился онлайн в июне 2008 г. с предисловием Михаила Горбачева, президента СССР, где были он выражал наилучшие пожелания журналу КТТ. На протяжении 2000-х годов М. С. Горбачев сделал большой вклад в развитие трансплантации костного мозга в России, профинансировал и обеспечил строительство НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, который открылся при Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в сентябре 2007 г. Таким образом, журнал КТТ явился существенной составной частью большой программы, направленной на развитие трансплантации гемопоэтических клеток в России и странах бывшего СССР и на обмен полезными данными с нашими западными коллегами. Публикации журнала КТТ предоставляли дополнительные ценные знания молодым специалистам из России, повышали их мотивацию и улучшали языковые навыки при написании их статей на английском языке. Статьи в КТТ также облегчали им защиту их диссертаций.<br>
Со времени основания журнала КТТ, его общая издательская политика состояла в публикации компетентных мнений, а также современных клинических и научных результатов, полученных российскими и западными клиницистами и исследователями. Как ранее, так и в настоящее время мы принимаем статьи, написанные по-английски с расширенными российскими резюме, тем самым привлекая авторов и читателей, как из бывшего СССР, так и западных стран.<br>
На протяжении этих лет мы гордились публикацией ряда исторических заметок об А. А. Максимове и А. Я. Фриденштейне и их инновационных идеях в гематологии, множеством аналитических обзоров о технологиях ТКМ, режимах терапии и новых лечебных препаратах, которые повышают терапевтическую эффективность и улучшают качество жизни пациентов, а также большим числом оригинальных статей. Каждый год КТТ публикует сводки презентаций и резюме докладов, представленных на ежегодном симпозиуме памяти Р. М. Горбачевой, посвященном трансплантации гемопоэтических клеток. Журнал КТТ реферируется в российских и западных базах данных (Scopus, ResearchGate, Google Scholar, E-library), а также находится в перечне изданий, где должны публиковаться статьи для соискателей кандидатской и докторской степеней признанных ВАК РФ.<br>
Редакционный совет нашего журнала представлен широко известными специалистами по ТКМ и смежным вопросам из разных стран. Особая благодарность сле дует выразить проф. Акселю Р. Цандеру, проф. Герарду Вагемакеру и проф. Борису Фезе за их постоянное участие в нашей совместной работе и издательской деятельности журнала КТТ. Мы надеемся, что общая политика и содержание нашего журнала будут сохраняться, тем самым способствуя распространению научных сведений о трансплантации и повышению уровня знаний о клеточной терапии в российских и европейских клиниках, особенно о современных технологиях, включая генную терапию, для блага пациентов с онкогематологическими и наследственными заболеваниями.
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Общий замысел и основание нашего журнала «Клеточная Терапия и Трансплантация» (КТТ) базировались на долгосрочном сотрудничестве российских и европейских специалистов в области трансплантации костного мозга (ТКМ). Совместные исследования в смежных научных областях основывались на предыдущих контактах между российскими и европейскими гематологами, онкологами и экспертами в области молекулярной биологии и генной терапии с 1990-х гг. Ввиду тесных международных рабочих связей между врачами и программ подготовки молодых российских специалистов в зарубежных клиниках, проф. Борис В. Афанасьев, проф. Дж. Вагемакер, проф. Аксель Р. Цандер и другие известные специалисты признали необходимость специального международного издания для лучшего сотрудничества в данной области. Генеральная концепция журнала «Клеточная Терапия и Трансплантация» была разработана в ходе дискуссий на встречах в Вильседе и Европейской группы ТКМ в 2006-2008 гг.
Поэтому пилотный выпуск КТТ появился онлайн в июне 2008 г. с предисловием Михаила Горбачева, президента СССР, где были он выражал наилучшие пожелания журналу КТТ. На протяжении 2000-х годов М. С. Горбачев сделал большой вклад в развитие трансплантации костного мозга в России, профинансировал и обеспечил строительство НИИ детской онкологии, гематологии и трансплантации им. Р. М. Горбачевой, который открылся при Первом Санкт-Петербургском государственном медицинском университете им. И. П. Павлова в сентябре 2007 г. Таким образом, журнал КТТ явился существенной составной частью большой программы, направленной на развитие трансплантации гемопоэтических клеток в России и странах бывшего СССР и на обмен полезными данными с нашими западными коллегами. Публикации журнала КТТ предоставляли дополнительные ценные знания молодым специалистам из России, повышали их мотивацию и улучшали языковые навыки при написании их статей на английском языке. Статьи в КТТ также облегчали им защиту их диссертаций.
Со времени основания журнала КТТ, его общая издательская политика состояла в публикации компетентных мнений, а также современных клинических и научных результатов, полученных российскими и западными клиницистами и исследователями. Как ранее, так и в настоящее время мы принимаем статьи, написанные по-английски с расширенными российскими резюме, тем самым привлекая авторов и читателей, как из бывшего СССР, так и западных стран.
На протяжении этих лет мы гордились публикацией ряда исторических заметок об А. А. Максимове и А. Я. Фриденштейне и их инновационных идеях в гематологии, множеством аналитических обзоров о технологиях ТКМ, режимах терапии и новых лечебных препаратах, которые повышают терапевтическую эффективность и улучшают качество жизни пациентов, а также большим числом оригинальных статей. Каждый год КТТ публикует сводки презентаций и резюме докладов, представленных на ежегодном симпозиуме памяти Р. М. Горбачевой, посвященном трансплантации гемопоэтических клеток. Журнал КТТ реферируется в российских и западных базах данных (Scopus, ResearchGate, Google Scholar, E-library), а также находится в перечне изданий, где должны публиковаться статьи для соискателей кандидатской и докторской степеней признанных ВАК РФ.
Редакционный совет нашего журнала представлен широко известными специалистами по ТКМ и смежным вопросам из разных стран. Особая благодарность сле дует выразить проф. Акселю Р. Цандеру, проф. Герарду Вагемакеру и проф. Борису Фезе за их постоянное участие в нашей совместной работе и издательской деятельности журнала КТТ. Мы надеемся, что общая политика и содержание нашего журнала будут сохраняться, тем самым способствуя распространению научных сведений о трансплантации и повышению уровня знаний о клеточной терапии в российских и европейских клиниках, особенно о современных технологиях, включая генную терапию, для блага пациентов с онкогематологическими и наследственными заболеваниями.
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The general idea and foundation of our Cellular Therapy and Transplantation Journal (CTT) were based on a long-term cooperation between Russian and European specialists in the area of bone marrow transplantation (BMT). Common studies in adjacent research topics stemmed from previous contacts between the Russian and European hematologists, oncologists, and experts in the fi eld of molecular biology and gene therapy since 1990s. In view of close working contacts between the clinicians from diff erent countries, and training programs for young Russian specialists in foreign clinics, a need for a special international edition for better cooperation was recognized by Prof. Boris V. Afanasyev, Prof. G. Wagemaker, Prof. Axel R. Zander and other prominent workers in the fi eld. The general concept of Cellular Therapy and Transplantation was elaborated during discussions at the Wilsede and EBMT Meetings in 2006-2008.<br>
Therefore, the pilot CTT issue appeared online in June 2008, preceded by a foreword by Mr. Michael Gorbachev, the former Russian President who expressed his best wishes to the CTT Journal. Over 2000s Michael Gorbachev contributed much to development of BMT in Russia, by funding and construction of the R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation which was opened at the St. Petersburg State I. Pavlov Medical University in September 2007. Hence, the CTT Journal proved to be a suffi cient part of a big program aimed for development of hematopoietic transplantation in Russia and ex-USSR countries, and exchange of useful data with our Western colleagues. The CTT publications provided additional valuable knowledge for the young specialists from Russia, increased their motivation, and improved language skills when preparing their articles in English. The CTT articles also facilitated their Ph.D. defense.<br>
Since launching the CTT Journal, its general editorial policy was to publish competent opinions, as well as modern clinical and research results obtained by Russian and Western clinicians and researchers. Then and now, we accept articles written in English language with extended Russian summaries, thus attracting authors and readership of both ex-USSR and Western countries.<br>
Over these years, we have been proud of publishing some historical notes about A. A. Maximov, and A. Ya. Friedenstein and their innovative ideas in hematology, a number of comprehensive reviews on the BMT techniques, treatment regimens and novel curative drugs which increase therapeutic efficiency and improve quality of life in the patients, as well as a number of original articles. Every year, CTT publishes the abstracts of presentations and short reports from the R. Gorbacheva Memorial Symposium dedicated to hematopoietic stem cell transplantation. The CTT Journal is referred in Russian and Western databases (Scopus, Research-Gate, Google Scholar, E-library), being approved by the Russian State Commission for Academic Degrees and Titles.<br>
Our Editorial Board is presented by the well-known specialists in BMT and related topics from diff erent countries. A special gratitude should be expressed to Professor Axel R. Zander, Prof. Gerard Wagemaker, and Prof. Boris Fehse for their long-range participation in our cooperation and the CTT editorial activities. We hope that the general policy and content of the Journal will retain, thus further promoting dissipation of transplantation science and improving knowledge in cell therapy in Russian and European clinics, especially, modern technologies, including gene therapy, for the sake of patients with oncohematological diseases and inherited disorders.
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The general idea and foundation of our Cellular Therapy and Transplantation Journal (CTT) were based on a long-term cooperation between Russian and European specialists in the area of bone marrow transplantation (BMT). Common studies in adjacent research topics stemmed from previous contacts between the Russian and European hematologists, oncologists, and experts in the fi eld of molecular biology and gene therapy since 1990s. In view of close working contacts between the clinicians from diff erent countries, and training programs for young Russian specialists in foreign clinics, a need for a special international edition for better cooperation was recognized by Prof. Boris V. Afanasyev, Prof. G. Wagemaker, Prof. Axel R. Zander and other prominent workers in the fi eld. The general concept of Cellular Therapy and Transplantation was elaborated during discussions at the Wilsede and EBMT Meetings in 2006-2008.
Therefore, the pilot CTT issue appeared online in June 2008, preceded by a foreword by Mr. Michael Gorbachev, the former Russian President who expressed his best wishes to the CTT Journal. Over 2000s Michael Gorbachev contributed much to development of BMT in Russia, by funding and construction of the R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation which was opened at the St. Petersburg State I. Pavlov Medical University in September 2007. Hence, the CTT Journal proved to be a suffi cient part of a big program aimed for development of hematopoietic transplantation in Russia and ex-USSR countries, and exchange of useful data with our Western colleagues. The CTT publications provided additional valuable knowledge for the young specialists from Russia, increased their motivation, and improved language skills when preparing their articles in English. The CTT articles also facilitated their Ph.D. defense.
Since launching the CTT Journal, its general editorial policy was to publish competent opinions, as well as modern clinical and research results obtained by Russian and Western clinicians and researchers. Then and now, we accept articles written in English language with extended Russian summaries, thus attracting authors and readership of both ex-USSR and Western countries.
Over these years, we have been proud of publishing some historical notes about A. A. Maximov, and A. Ya. Friedenstein and their innovative ideas in hematology, a number of comprehensive reviews on the BMT techniques, treatment regimens and novel curative drugs which increase therapeutic efficiency and improve quality of life in the patients, as well as a number of original articles. Every year, CTT publishes the abstracts of presentations and short reports from the R. Gorbacheva Memorial Symposium dedicated to hematopoietic stem cell transplantation. The CTT Journal is referred in Russian and Western databases (Scopus, Research-Gate, Google Scholar, E-library), being approved by the Russian State Commission for Academic Degrees and Titles.
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Professor Boris V. Afanasyev, Editor-in-Chief, Cellular Therapy and Transplantation Journal
The general idea and foundation of our Cellular Therapy and Transplantation Journal (CTT) were based on a long-term cooperation between Russian and European specialists in the area of bone marrow transplantation (BMT). Common studies in adjacent research topics stemmed from previous contacts between the Russian and European hematologists, oncologists, and experts in the fi eld of molecular biology and gene therapy since 1990s. In view of close working contacts between the clinicians from diff erent countries, and training programs for young Russian specialists in foreign clinics, a need for a special international edition for better cooperation was recognized by Prof. Boris V. Afanasyev, Prof. G. Wagemaker, Prof. Axel R. Zander and other prominent workers in the fi eld. The general concept of Cellular Therapy and Transplantation was elaborated during discussions at the Wilsede and EBMT Meetings in 2006-2008.
Therefore, the pilot CTT issue appeared online in June 2008, preceded by a foreword by Mr. Michael Gorbachev, the former Russian President who expressed his best wishes to the CTT Journal. Over 2000s Michael Gorbachev contributed much to development of BMT in Russia, by funding and construction of the R. M. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation which was opened at the St. Petersburg State I. Pavlov Medical University in September 2007. Hence, the CTT Journal proved to be a suffi cient part of a big program aimed for development of hematopoietic transplantation in Russia and ex-USSR countries, and exchange of useful data with our Western colleagues. The CTT publications provided additional valuable knowledge for the young specialists from Russia, increased their motivation, and improved language skills when preparing their articles in English. The CTT articles also facilitated their Ph.D. defense.
Since launching the CTT Journal, its general editorial policy was to publish competent opinions, as well as modern clinical and research results obtained by Russian and Western clinicians and researchers. Then and now, we accept articles written in English language with extended Russian summaries, thus attracting authors and readership of both ex-USSR and Western countries.
Over these years, we have been proud of publishing some historical notes about A. A. Maximov, and A. Ya. Friedenstein and their innovative ideas in hematology, a number of comprehensive reviews on the BMT techniques, treatment regimens and novel curative drugs which increase therapeutic efficiency and improve quality of life in the patients, as well as a number of original articles. Every year, CTT publishes the abstracts of presentations and short reports from the R. Gorbacheva Memorial Symposium dedicated to hematopoietic stem cell transplantation. The CTT Journal is referred in Russian and Western databases (Scopus, Research-Gate, Google Scholar, E-library), being approved by the Russian State Commission for Academic Degrees and Titles.
Our Editorial Board is presented by the well-known specialists in BMT and related topics from diff erent countries. A special gratitude should be expressed to Professor Axel R. Zander, Prof. Gerard Wagemaker, and Prof. Boris Fehse for their long-range participation in our cooperation and the CTT editorial activities. We hope that the general policy and content of the Journal will retain, thus further promoting dissipation of transplantation science and improving knowledge in cell therapy in Russian and European clinics, especially, modern technologies, including gene therapy, for the sake of patients with oncohematological diseases and inherited disorders.
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Интенсивная цитостатическая терапия применяется в качестве стандартной терапии злокачественных новообразований гемопоэтической системы. Кондиционирующая терапия перед трансплантацией гемопоэтических стволовых клеток (ТГСК) приводит как к острому клеточному иммунодефициту, так и к тяжелым нарушениям кишечного эпителия, а массивная антибактериальная терапия ведет к глубоким нарушениям состава кишечной микрофлоры. Целью настоящего обзора было уточнение генетических факторов, внешних воздействий и терапевтических факторов, вызывающих изменения кишечной микробиоты в процессе интенсивной цитостатической терапии, обозначение возможных подходов к нормализации кишечного микробиома при ТГСК. Обсуждаются ранние эксперименты с безмикробными животными, описываются общепринятые взгляды на «нормальную» микробиоту кишечника человека, ее вариабельность и изменения, зависящие от возраста, диеты и генетической предрасположенности по основным классам кишечной микробиоты, т. е., анаэробных Clostridia, и более аэробных Bacteroides, Proteobacteria. Измененный состав и снижение биоразнообразия кишечной микробиоты рассматривается в качестве регулярного следствия цитостатической и антибактериальной терапии в период ТГСК. Роль порозности кишечной стенки и соответствующие эффекты на иммунную систему организма-хозяина рассматриваются в аспекте риска реакции «трансплантат против хозяина», а также возможных антирецидивных эффектов при лейкозах, связанных с изменениями состава кишечной микробиоты. Обсуждаются некоторые гены, влияющие на кишечную микробиоту, например – влияние ATG16L1, PD-1, FUT2 и других генных вариантов, которые могут влиять на эффективность ТГСК.<br>
Потенциальная роль многочисленных кишечных вирусов («вирома») известна в значительно меньшей степени, в связи с относительной нехваткой данных, полученных путем секвенирования следующего поколения (NGS) бактериофагов и вирусов эукариотических клеток.<br>
В заключение отмечено, что многие факты о кишечной микробиоте требуют особой оценки у человека при его лечении. Проведен ряд работ, направленных на коррекцию измененной кишечной микробиоты при различных кишечных синдромах, в том числе – с использованием отдельных пробиотических штаммов Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, и в последнее время – трансплантации фекальной микробиоты, в том числе и при дисбиозе после ТГСК. Основная проблема состоит в том, что при анализе сложных взаимодействий бактериальной микробиоты в клинических условиях мы еще не знаем, какие именно микробные виды (или классы) продуцируют эффекторные молекулы, которые модифицируют иммунный ответ, ведущий к тяжелой РТПХ или изменяющий противоопухолевый ответ иммунотерапии. Для соответствующих сравнений со здоровыми людьми следует устанавливать нормальные области значений для конкретных классов кишечной микробиоты в различных возрастных группах.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Микробиом, кишечный, кишечные бактерии, виром, трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, антибактериальное лечение, подавление микрофлоры, трансплантация кишечной микробиоты.
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Интенсивная цитостатическая терапия применяется в качестве стандартной терапии злокачественных новообразований гемопоэтической системы. Кондиционирующая терапия перед трансплантацией гемопоэтических стволовых клеток (ТГСК) приводит как к острому клеточному иммунодефициту, так и к тяжелым нарушениям кишечного эпителия, а массивная антибактериальная терапия ведет к глубоким нарушениям состава кишечной микрофлоры. Целью настоящего обзора было уточнение генетических факторов, внешних воздействий и терапевтических факторов, вызывающих изменения кишечной микробиоты в процессе интенсивной цитостатической терапии, обозначение возможных подходов к нормализации кишечного микробиома при ТГСК. Обсуждаются ранние эксперименты с безмикробными животными, описываются общепринятые взгляды на «нормальную» микробиоту кишечника человека, ее вариабельность и изменения, зависящие от возраста, диеты и генетической предрасположенности по основным классам кишечной микробиоты, т. е., анаэробных Clostridia, и более аэробных Bacteroides, Proteobacteria. Измененный состав и снижение биоразнообразия кишечной микробиоты рассматривается в качестве регулярного следствия цитостатической и антибактериальной терапии в период ТГСК. Роль порозности кишечной стенки и соответствующие эффекты на иммунную систему организма-хозяина рассматриваются в аспекте риска реакции «трансплантат против хозяина», а также возможных антирецидивных эффектов при лейкозах, связанных с изменениями состава кишечной микробиоты. Обсуждаются некоторые гены, влияющие на кишечную микробиоту, например – влияние ATG16L1, PD-1, FUT2 и других генных вариантов, которые могут влиять на эффективность ТГСК.
Потенциальная роль многочисленных кишечных вирусов («вирома») известна в значительно меньшей степени, в связи с относительной нехваткой данных, полученных путем секвенирования следующего поколения (NGS) бактериофагов и вирусов эукариотических клеток.
В заключение отмечено, что многие факты о кишечной микробиоте требуют особой оценки у человека при его лечении. Проведен ряд работ, направленных на коррекцию измененной кишечной микробиоты при различных кишечных синдромах, в том числе – с использованием отдельных пробиотических штаммов Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, и в последнее время – трансплантации фекальной микробиоты, в том числе и при дисбиозе после ТГСК. Основная проблема состоит в том, что при анализе сложных взаимодействий бактериальной микробиоты в клинических условиях мы еще не знаем, какие именно микробные виды (или классы) продуцируют эффекторные молекулы, которые модифицируют иммунный ответ, ведущий к тяжелой РТПХ или изменяющий противоопухолевый ответ иммунотерапии. Для соответствующих сравнений со здоровыми людьми следует устанавливать нормальные области значений для конкретных классов кишечной микробиоты в различных возрастных группах.
Ключевые слова
Микробиом, кишечный, кишечные бактерии, виром, трансплантация гемопоэтических стволовых клеток, цитостатическая терапия, антибактериальное лечение, подавление микрофлоры, трансплантация кишечной микробиоты.
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Intensive cytostatic therapy is applied as a standard treatment in malignant disorders of hematopoiesis. Conditioning treatment before allogeneic hematopoietic stem cell transplantation (HSCT) causes both acute cellular immune defi ciency and severe damage of gut epithelium, and massive antibacterial therapy lead to profound alterations of gut microfl ora composition. The aim of this review article was to specify environmental, genetic and treatment-related factors causing changes of gut microbiota in the course of intensive cytostatic therapy, delineating possible approaches to normalization of gut microbiome in HSCT. We discuss early experiments with germ-free organisms, describe common views on the “normal” human gut microbiota, its variability, and changes depending on age, dietary background and genetic predisposal between the main classes of gut microbiota, i.e., anaerobic Clostridia, and mostly aerobic Bacteroides, Proteobacteria. Changed composition and decreased biodiversity of gut microfl ora is regarded as a regular consequence of cytostatic and antibacterial therapies during the HSCT procedure. Role of enteric leakage, and eff ects upon immune system of host are considered in view of graft -versus-disease risk, as well as anti-cancer eff ects associated with altered composition of intestinal microbiota. Some genes aff ecting gut microbiota are discussed, e.g., eff ects of ATG16L1, PD-1, FUT2 and some other gene variants which may alter efficiency of HSCT.<br>
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In conclusion, many facts concerning gut microbiota require specifi c evaluation in human patients. E.g., a number of works was performed in order to correct altered gut microbiota in various intestinal syndromes, including specifi c probiotic strains of Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, and more recently, fecal microbiota transplantation, also in the post-HSCT dysbiosis. Th e main issue is that, when dealing with complex bacterial network of microbiota in clinical settings, we still do not know what exact microbial species (or classes) are producing eff ector molecules which modify immune response causing severe GvHD or changing the antitumor eff ects of immune therapy. To compare them with healthy subjects, the normal ranges should be established for distinct classes of intestinal microbiota within diff erent age groups.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Microbiome, intestinal, gut bacteria, virome, hematopoietic stem cell transplantation, cytostatic therapy, antibacterial treatment, microfl ora suppression, gut microbiota transplantation.
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Intensive cytostatic therapy is applied as a standard treatment in malignant disorders of hematopoiesis. Conditioning treatment before allogeneic hematopoietic stem cell transplantation (HSCT) causes both acute cellular immune defi ciency and severe damage of gut epithelium, and massive antibacterial therapy lead to profound alterations of gut microfl ora composition. The aim of this review article was to specify environmental, genetic and treatment-related factors causing changes of gut microbiota in the course of intensive cytostatic therapy, delineating possible approaches to normalization of gut microbiome in HSCT. We discuss early experiments with germ-free organisms, describe common views on the “normal” human gut microbiota, its variability, and changes depending on age, dietary background and genetic predisposal between the main classes of gut microbiota, i.e., anaerobic Clostridia, and mostly aerobic Bacteroides, Proteobacteria. Changed composition and decreased biodiversity of gut microfl ora is regarded as a regular consequence of cytostatic and antibacterial therapies during the HSCT procedure. Role of enteric leakage, and eff ects upon immune system of host are considered in view of graft -versus-disease risk, as well as anti-cancer eff ects associated with altered composition of intestinal microbiota. Some genes aff ecting gut microbiota are discussed, e.g., eff ects of ATG16L1, PD-1, FUT2 and some other gene variants which may alter efficiency of HSCT.
Potential role of multiple gut viruses (virome) is known to much lesser degree, due to relative lack of data derived from next-generation sequencing (NGS) of bacteriophages and eukaryotic cell viruses.
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Keywords
Microbiome, intestinal, gut bacteria, virome, hematopoietic stem cell transplantation, cytostatic therapy, antibacterial treatment, microfl ora suppression, gut microbiota transplantation.
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Oleg V. Goloshchapov, Maxim A. Kucher, Alexey B. Chukhlovin
`
Intensive cytostatic therapy is applied as a standard treatment in malignant disorders of hematopoiesis. Conditioning treatment before allogeneic hematopoietic stem cell transplantation (HSCT) causes both acute cellular immune defi ciency and severe damage of gut epithelium, and massive antibacterial therapy lead to profound alterations of gut microfl ora composition. The aim of this review article was to specify environmental, genetic and treatment-related factors causing changes of gut microbiota in the course of intensive cytostatic therapy, delineating possible approaches to normalization of gut microbiome in HSCT. We discuss early experiments with germ-free organisms, describe common views on the “normal” human gut microbiota, its variability, and changes depending on age, dietary background and genetic predisposal between the main classes of gut microbiota, i.e., anaerobic Clostridia, and mostly aerobic Bacteroides, Proteobacteria. Changed composition and decreased biodiversity of gut microfl ora is regarded as a regular consequence of cytostatic and antibacterial therapies during the HSCT procedure. Role of enteric leakage, and eff ects upon immune system of host are considered in view of graft -versus-disease risk, as well as anti-cancer eff ects associated with altered composition of intestinal microbiota. Some genes aff ecting gut microbiota are discussed, e.g., eff ects of ATG16L1, PD-1, FUT2 and some other gene variants which may alter efficiency of HSCT.
Potential role of multiple gut viruses (virome) is known to much lesser degree, due to relative lack of data derived from next-generation sequencing (NGS) of bacteriophages and eukaryotic cell viruses.
In conclusion, many facts concerning gut microbiota require specifi c evaluation in human patients. E.g., a number of works was performed in order to correct altered gut microbiota in various intestinal syndromes, including specifi c probiotic strains of Lactobacteria, Bifi dobacteria, Faecalibacterium prausnitzii, and more recently, fecal microbiota transplantation, also in the post-HSCT dysbiosis. Th e main issue is that, when dealing with complex bacterial network of microbiota in clinical settings, we still do not know what exact microbial species (or classes) are producing eff ector molecules which modify immune response causing severe GvHD or changing the antitumor eff ects of immune therapy. To compare them with healthy subjects, the normal ranges should be established for distinct classes of intestinal microbiota within diff erent age groups.
Keywords
Microbiome, intestinal, gut bacteria, virome, hematopoietic stem cell transplantation, cytostatic therapy, antibacterial treatment, microfl ora suppression, gut microbiota transplantation.
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Миеломная болезнь (МБ) остается пока неизлечимым злокачественным заболеванием, не отвечающим в полной мере на множество видов химио- и иммунотерапевтических методов лечения. В США ежегодно диагностируются более 20000 случаев. Трансплантация костного мозга все еще рассматривается как основной метод лечения МБ, по крайней мере в настоящее время. Очевидной необходимостью является повторное рассмотрение старых подходов к лечению с применением клеточной терапии, таких, как аутологичная или аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) и разработка новых опций, таких, как использование CAR-T-клеток.<br>
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<h2 style="text-align: justify;">Ключевые слова</h2>
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Ключевые слова
Множественная миелома, аллогенная трансплантация, аутологичная трансплантация, CAR T-клетки.
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[TEXT] => <sup>1</sup> Alfaisal University, Riyadh, KSA<br>
<sup>2</sup> Department of Stem Cell Transplant, Huntsman Cancer Center Institute, SLC, USA<br>
<sup>3</sup> University of Hamburg, Germany
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3 University of Hamburg, Germany
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Multiple myeloma is still an incurable cancer notwithstanding the myriads of chemo-and immunotherapies, There are more than 20,000 cases of MM diagnosed per year in the US. Bone marrow transplant is still considered the cornerstone for MM therapy, at least for now. The evident need is to revisit the conventional treatment approaches to cellular therapy, such as auto- and/or allogeneic hematopoietic stem cell transplantation (HCT), and develop the new options, like CAR-T cells. This review article will present and discuss diff erent approaches to modern treatment of MM, by summarizing the results of clinical studies, raising feasibility and effi ciency questions, and answering some of them which have been already resolved in numerous trials performed with CAR-T cells.
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<h2 style="text-align: justify;">Keywords</h2>
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Multiple myeloma, allogeneic transplant, autologous transplant, CAR-T cells.
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Multiple myeloma is still an incurable cancer notwithstanding the myriads of chemo-and immunotherapies, There are more than 20,000 cases of MM diagnosed per year in the US. Bone marrow transplant is still considered the cornerstone for MM therapy, at least for now. The evident need is to revisit the conventional treatment approaches to cellular therapy, such as auto- and/or allogeneic hematopoietic stem cell transplantation (HCT), and develop the new options, like CAR-T cells. This review article will present and discuss diff erent approaches to modern treatment of MM, by summarizing the results of clinical studies, raising feasibility and effi ciency questions, and answering some of them which have been already resolved in numerous trials performed with CAR-T cells.
Keywords
Multiple myeloma, allogeneic transplant, autologous transplant, CAR-T cells.
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Nouran Sabbagh1, Axel R. Zander 2,3
2 Department of Stem Cell Transplant, Huntsman Cancer Center Institute, SLC, USA
3 University of Hamburg, Germany
Multiple myeloma is still an incurable cancer notwithstanding the myriads of chemo-and immunotherapies, There are more than 20,000 cases of MM diagnosed per year in the US. Bone marrow transplant is still considered the cornerstone for MM therapy, at least for now. The evident need is to revisit the conventional treatment approaches to cellular therapy, such as auto- and/or allogeneic hematopoietic stem cell transplantation (HCT), and develop the new options, like CAR-T cells. This review article will present and discuss diff erent approaches to modern treatment of MM, by summarizing the results of clinical studies, raising feasibility and effi ciency questions, and answering some of them which have been already resolved in numerous trials performed with CAR-T cells.
Keywords
Multiple myeloma, allogeneic transplant, autologous transplant, CAR-T cells.
Clinical studies
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Изменения технологии аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК), например, внедрение заготовки периферических стволовых клеток крови (СКПК) и трансплантация от неродственного донора привели к значимым изменениям факторов риска реакции «трансплантат против хозяина» (РТПХ). В настоящий момент ограничено число публикаций, оценивавших влияние новых режимов профилактики РТПХ на факторы риска этого осложнения. Было проведено исследование на двух когортах пациентов. В первую, с классической профилактикой РТПХ вошло 199/344 родственных и неродственных трансплантаций, соответственно, с профилактикой ингибиторами кальциневрина с метотрексатом/ММФ±атитимоцитарный глобулином. Во вторую когорту пациентов вошли 104/365 родственных и неродственных трансплантаций, соответственно, с профилактикой посттрансплантационным циклофосфаном (ПТЦф) в качестве монотерапии или в комбинации с такролимусом и ММФ. При классической профилактике значимыми оказались трансплантация от неродственного донора (HR 1.86, 95%CI 1.11-3.19, p=0.0219), принадлежность к группе спасения (HR 0.50, 95%CI 0.30-0.79), использование режимов кондиционирования со сниженной токсичностью (HR 0.58, 95%CI 0.40-0.85), пожилой возраст (HR 0.0442, 95%CI 0.96-0.99), высокий ИМТ (HR 0.97, 95%CI 0.97-1.00) и раннее приживление (HR 1.55, 95%CI 1.08-2.22). Для ПТЦф единственным значимым фактором оказался цитомегаловирусный серостатус донора и реципиента (HR 0.71, 95%CI 0.54-0.95, p=0.0251). Для хронической РТПХ средней и тяжелой степени при классической профилактике выявлены следующие факторы риска: использование СКПК (HR 2.26, 95%CI 1.28-4.11) и наличие предшествовавшей острой РТПХ (HR 3.76, 95%CI 2.32-6.37). Для профилактики с ПТЦф ни одного значимого фактора риска не выявлено. Слабую статистическую взаимосвязь демонстрировал анамнез острой РТПХ (HR 1.59, 95%CI 0.99-2.54). В заключении, исследование продемонстрировало значимые различия в факторах риска РТПХ между классической профилактикой и профилактикой на основе ПТЦф. Требуются дальнейшие исследования для изучения биологических основ этих различий.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.
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Ключевые слова
Реакция «трансплантат против хозяина», факторы риска, посттрансплантационный циклофосфан.
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Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.
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Keywords
Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.
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Ivan S. Moiseev, Elena I. Darskaya, Tatyana A. Bykova, Elena V. Morozova, Alexander L. Alyanskiy, Elena V. Babenko, Sergey N. Bondarenko, Inna V. Markova, Boris V. Afanasyev
Novel aspects of allogeneic stem cell transplantation (HSCT) technologies, like use of peripheral blood stem cells (PBSC), or usage of unrelated donors significantly change the risk factors of graft -versus-host disease. Little is known, whether novel prophylaxis regimens also alter the risk factor pattern. In this study we evaluated risk factors of grade II-IV acute GVHD, and moderate or severe (NIH) chronic GVHD in the cohort of 199/344 related/ unrelated patients subjected to conventional prophylaxis with calcineurin inhibitor plus methotrexate/mycophenolate mofetil (MMF) ± antithymocyte globuline. Another cohort included 104/365 recipients of related/unrelated graft s with either single-agent posttransplant cyclophosphamide (PTCy), or its combination with tacrolimus and MMF, respectively. We have observed that, for the conventional prophylaxis, the signifi cant factors for acute GVHD were unrelated donor (HR 1.86, 95%CI 1.11-3.19, p=0.0219), salvage disease status at transplant (HR 0.50, 95%CI 0.30-0.79), use of RIC (HR 0.58, 95%CI 0.40-0.85), older age (HR 0.0442, 95%CI 0.96- 0.99), higher BMI (HR 0.97, 95%CI 0.97-1.00) and early engraft ment (HR 1.55, 95%CI 1.08-2.22). For PTCy prophylaxis, cytomegalovirus serostatus was the only signifi cant factor (HR 0.71, 95%CI 0.54-0.95, p=0.0251). The risk factors of moderate and severe chronic GVHD aft er conventional prophylaxis were PBSC graft (HR 2.26, 95%CI 1.28-4.11) and previous acute GVHD (HR 3.76, 95%CI 2.32-6.37), while no significant factors were identified for the PTCy prophylaxis. A weak association was found with previous acute GVHD (HR 1.59, 95%CI 0.99-2.54). In conclusion, we have identified the different pattern of GVHD risk factors with conventional prophylaxis and PTCy in related and unrelated donors. Further studies are required to identify the mechanisms behind these observations.
Keywords
Graft -versus-host disease, risk factors, posttransplantation cyclophosphamide.
Clinical studies
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[TEXT] => <sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова» Министерства здравоохранения России<br>
<sup>2</sup> Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия<br>
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[TEXT] => 1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова» Министерства здравоохранения России
2 Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия
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В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.
</p>
<h2 style="text-align: justify;">Пациенты и методы</h2>
<p style="text-align: justify;">
В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).
</p>
<h2 style="text-align: justify;">Результаты</h2>
<p style="text-align: justify;">
АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.
</p>
<h2 style="text-align: justify;">Заключение</h2>
<p style="text-align: justify;">
АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что<br>
требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.
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В настоящее время существуют противоречивые данные о негативном влиянии АВО-несовместимости на вероятность развития осложнений и эффективность лечения при аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК). Целью работы было изучение роли антигенов АВО-несовместимости при алло-ТГСК.
Пациенты и методы
В исследование включено 1132 пациента с гематологическими, онкологическими и наследственными заболеваниями, которым было выполнено 1482 алло-ТГСК. Возраст составил 6 месяцев – 76 лет, медиана – 25 лет. Проведен комплексный статистический анализ, направленный на определение влияния АВО-несовместимости как изолированного фактора, так и в комбинации с другими факторами при алло-ТГСК в различных группах сравнения, созданы прогностические модели общей выживаемости (ОВ).
Результаты
АВО-несовместимость определялась в 54,6% случаев (n=780): большая – 37,8% (n=295); малая – 45,4% (n=354); комбинированная – 16,8% (n=131). У пациентов с лейкозами негативное влияние на ОВ Д+100 оказала малая АВО-несовместимость по сравнению с АВО-совместимыми алло-ТГСК – 85% и 91%, p=0,05. Комбинация миелоаблативного режима кондиционирования и большой АВО-несовместимости (n=37) в раннем периоде (Д+100) снижала ОВ по сравнению с АВО-совместимыми ТГСК (n=103) – 76% и 91%, p=0,025. Наличие АВО-несовместимости не увеличивало вероятность развития острой и хронической реакции «трансплантат против хозяина» у пациентов с лейкозами, p=0,85.
Заключение
АВО-несовместимость может приводить к снижению эффективности лечения при алло-ТГСК в раннем периоде и в течение первого года при совпадении ряда взаимопотенцирующих факторов, что
требует выбора АВО-совместимого донора гемопоэтических стволовых клеток при наличии такой возможности и предъявляет повышенные требования иммуногематологической безопасности при заместительных трансфузиях компонентов крови.
Ключевые слова
Трансплантация гемопоэтических стволовых клеток, АВО-несовместимость, осложнения.
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[TEXT] => Maxim A. Kucher <sup>1</sup>, Dmitrii E. Pevtcov <sup>1</sup>, Polina S. Kuga <sup>1</sup>, Boris I. Smirnov <sup>1</sup>,<sup>2</sup>, Alexander L. Alyanskiy <sup>1</sup>, Natalia E. Ivanova 1, Maria A. Estrina <sup>1</sup>, Elena V. Babenko <sup>1</sup>, Burkhonidin B. Bakhovadinov <sup>1</sup>, Ludmila S. Zubarovskaya <sup>1</sup>, Boris V. Afanasyev <sup>1</sup><br>
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[TEXT] => <sup>1</sup> R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St.P etersburg, Russia<br>
<sup>2</sup> St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia<br>
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[TEXT] => 1 R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St.P etersburg, Russia
2 St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
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Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.
</p>
<h2 style="text-align: justify;">Patients and methods</h2>
<p style="text-align: justify;">
From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.
</p>
<h2 style="text-align: justify;">Results</h2>
<p style="text-align: justify;">
ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.
</p>
<h2 style="text-align: justify;">Conclusion</h2>
<p style="text-align: justify;">
ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of<br>
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Hematopoietic stem cell transplantation, ABО-incompatibility, complications.
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Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.
Patients and methods
From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.
Results
ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.
Conclusion
ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.
Keywords
Hematopoietic stem cell transplantation, ABО-incompatibility, complications.
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Maxim A. Kucher 1, Dmitrii E. Pevtcov 1, Polina S. Kuga 1, Boris I. Smirnov 1,2, Alexander L. Alyanskiy 1, Natalia E. Ivanova 1, Maria A. Estrina 1, Elena V. Babenko 1, Burkhonidin B. Bakhovadinov 1, Ludmila S. Zubarovskaya 1, Boris V. Afanasyev 1
2 St. Petersburg State Electrotechnical University «LETI», St. Petersburg, Russia
Currently, there are confl icting data on the impact of recipient/donor ABO-incompatibility upon development of complications and eff ectiveness of treatment in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Th e aim of our study was to specify the role of ABO- and Rh- incompatibility in allo-HSCT for a well-characterized cohort of patients.
Patients and methods
From 1999 to 2015, 1132 patients with malignancies and hereditary diseases were subjected to 1482 allo-HSCTs at the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation. Th eir age was from 6 months to 76 years, at a median of 25 years old. A comprehensive statistical analysis in diff erent comparison groups was carried out, in order to determine the impact of ABO-incompatibility, either as isolated fi nding, or in combination with other factors, upon overall survival (OS), time and ability of engraft ment, posttransplant complications, i.e., hemolytic conditions, acute and chronic graft -versus-host disease (GvHD) observed in the allo-HSCT patients. Predictive models of OS were created.
Results
ABO-incompatibility was determined in 54.6% of cases (n=780): major – 37.8% (n=295); minor – 45.4% (n=354); bidirectional – 16.8% (n=131). In patients with leukemia, a negative impact on OS D+100 was revealed for minor ABO-incompatibility, as compared to ABO-compatible allo-HSCT (respectively, 85% and 91%, p=0.05. Combination of myeloablative conditioning regimen and major ABO-incompatibility (n=37) was associated with reduced OS during early period (D+100) compared to ABO-compatible allo-HSCT (n=103, respectively, 76% and 91%, p=0.025). Th e presence of ABO-incompatibility did not increase the risk of acute and chronic GvHD in patients with leukemia, p=0.85.
Conclusion
ABO-incompatibility in combination with other mutually potentiating factors can correlate with decreased therapeutic effi ciency by the D+100, and during first year aft er allo-HSCT, thus requiring selection of
ABO-compatible graft donors, if possible, and demands for high-quality prophylaxis and sophisticated transfusion therapy to prevent hemolytic complications.
Keywords
Hematopoietic stem cell transplantation, ABО-incompatibility, complications.
Clinical studies
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[TEXT] => <sup>1</sup> Республиканский научно-практический центр детской онкологии, гематологии и иммунологии, Минск, Республика Беларусь<br>
<sup>2</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Российская Федерация<br>
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2 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой Первого Санкт-Петербургского государственного медицинского университета им. И. П. Павлова, Санкт-Петербург, Российская Федерация
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Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.
</p>
<h2 style="text-align: justify;">Пациенты и методы</h2>
<p style="text-align: justify;">
Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.
</p>
<h2 style="text-align: justify;">Выводы</h2>
<p style="text-align: justify;">
Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.
</p>
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Клинические рецидивы остаются основной причиной неудач в лечении детей с острым лимфобластным лейкозом (ОЛЛ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). К настоящему времени не подтверждена необходимость точной количественной оценки минимальной остаточной болезни (МОБ) после трансплантации. Целью настоящего исследования была оценка вклада диагностики МОБ в тактику лечения и исходы алло-ТГСК.
Пациенты и методы
Для мониторинга МОБ идентифицировали маркеры Ig/TCR у 37 из 45 больных (82,2%). Наличие МОБ высокой степени после алло-ТГСК было неблагоприятным прогностическим фактором для клинического исхода. Трехлетняя кумулятивная встречаемость (CI) рецидива заболевания в группах пациентов с негативными результатами оценки МОБ, уровнями МОБ ≤10-3 и >10-3 была, соответственно, 10,7±7,4%; 14,6 ±14,6%, и 100% (p<0,0001). Бессобытийная выживаемость (EFS) при этом составила 66,6±11,4% против 43,8±18,8% и 0%, соответственно (p=0,0012), тогда как общая выживаемость (ОВ) была 83,6±8,8%, по сравнению с 57,1±18,7% и 0% (p=0,0083) для групп с отсутствием МОБ, при ее уровнях ≤10-3 и >10-3. Наличие МОБ в сочетании с повышением уровней смешанного химеризма (СХ) сопровождались рецидивами почти во всех случаях. Падение уровней МОБ наиболее часто отмечалось у пациентов с полным донорским химеризмом при наличии реакции «трансплантат против хозяина (оРТПХ) или после переливания донорских лимфоцитов.
Выводы
Наличие МОБ после ТГСК является фактором неблагоприятного исхода по параметрам общей и бессобытийной выживаемости и ассоциировано с рецидивом ОЛЛ. Мы идентифицировали группу высокого риска рецидивов после алло-ТГСК среди больных ОЛЛ, а именно – пациентов с наличием МОБ и смешанного химеризма и отсутствием РТПХ, и/или больных с уровнями МОБ выше 10-3.
Ключевые слова
Острый лимфобластный лейкоз, трансплантации гемопоэтических стволовых клеток, минимальная остаточная болезнь, донорский химеризм, риск рецидивов.
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[TEXT] => <sup>1</sup> Th e Republican Research and Practical Center of Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus<br>
<sup>2</sup> R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation
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[TEXT] => 1 Th e Republican Research and Practical Center of Pediatric Oncology, Hematology and Immunology, Minsk, Republic of Belarus
2 R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation
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At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes<br>
aft er allo-HSCT.
</p>
<h2 style="text-align: justify;">Patients and methods</h2>
<p style="text-align: justify;">
The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.
</p>
<h2 style="text-align: justify;">Conclusion</h2>
<p style="text-align: justify;">
Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.
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At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes
aft er allo-HSCT.
Patients and methods
The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.
Conclusion
Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.
Keywords
Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.
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Victoria A. Lavrinenko 1, Alexandr N. Meleshko 1, Dmitry V. Lutskovich 1, Yulia E. Mareiko 1, Dmitriy V. Prudnikov 1, Mikhail V. Belevtsev 1, Olga V. Aleynikova 1, Ildar M. Barkhatov 2, Boris V. Afanasyev 2
2 R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russian Federation
At the present time, clinical relapses remain the major cause of treatment failure in children with acute lymphoblastic leukemia (ALL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, the requirements for precise quantifi cation of minimal residual disease (MRD) aft er HSCT were did not confirmed. Th e aim of this study was to evaluate the impact of MRD assays on management and prediction of outcomes
aft er allo-HSCT.
Patients and methods
The Ig/TCR markers were identifi ed for MRD monitoring in 37 (82.2%) of 45 patients. Presence of high-level MRD aft er allo-HSCT was an unfavorable prognostic factor for the clinical outcome. Th e 3-year cumulative incidence (CI) of relapse in the patients with negative MRD vs MRD levels of ≤10-3, and >10-3 proved to be 10.7±7.4%; 14.6±14.6%, and 100%, respectively (p<0.0001). Event-free survival (EFS) was 66.6±11.4% vs 43.8±18.8% vs 0% (p=0.0012) at the respective MRD levels, whereas overall survival (OS) was 83.6±8.8% vs 57.1±18.7% vs 0% (p=0.0083), resp., for undetectable, ≤10-3, and >10-3 MRD levels. MRD positivity combined with increasing mixed chimerism (MC) was followed by relapse in almost all cases. MRD clearance was more often observed in patients with full donor chimerism (FDC) having graft -versus-host disease (GvHD) posttransplant, or aft er donor lymphocyte infusion.
Conclusion
Positive MRD aft er HSCT is an unfavorable factor for OS and EFS, being associated with ALL re-occurrence. We identifi ed the high-risk group for relapses aft er allo-HSCT among ALL patients, i.e., those cases whichshowed MRD positivity with mixed chimerism (MC) and absence of GvHD, and/or had MRD>10-3.
Keywords
Acute lymphoblastic leukemia, hematopoietic stem celltransplantation, minimal residual disease, donor chimerism, relapse risk.
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[TEXT] => <sup>1</sup> Отделение хирургической онкологии, онкологический центр университета Мансура
<sup>2</sup> Отделение патологической анатомии, Факультет медицины, университет Мансура, Египет
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2 Отделение патологической анатомии, Факультет медицины, университет Мансура, Египет
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Вторичные злокачественные новообразования после трансплантации почек являются нередкими событиями. В этом сообщении мы рассматриваем одну из причин посттрансплантационной смертности. Сообщается о клиническом случае трансплантации почек с последующей иммуносупрессивной терапией и развитием через 11 лет синхронного плоскоклеточного рака кожи и папиллярной карциномы щитовидной железы, которые диагностировали и лечили в онкологическом центре университета Мансура.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Трансплантация почек, иммуносупрессивные препараты, синхронные злокачественные опухоли.
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Вторичные злокачественные новообразования после трансплантации почек являются нередкими событиями. В этом сообщении мы рассматриваем одну из причин посттрансплантационной смертности. Сообщается о клиническом случае трансплантации почек с последующей иммуносупрессивной терапией и развитием через 11 лет синхронного плоскоклеточного рака кожи и папиллярной карциномы щитовидной железы, которые диагностировали и лечили в онкологическом центре университета Мансура.
Ключевые слова
Трансплантация почек, иммуносупрессивные препараты, синхронные злокачественные опухоли.
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Secondary malignancies following renal transplantation are not an uncommon event. In this report we considered one of the causes of posttransplant mortality. We report a renal transplant case and immune suppression treatment followed 11 years later by synchronous skin squamous cell carcinoma and papillary thyroid carcinoma that was diagnosed, presented and managed at the Oncology Center at Mansoura University.
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Kidney transplantation, immunosuppressive drugs, synchronous malignancy.
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Omar Hamdy 1, Sara Raafat 2, Amr Abouzid 1, Mahmoud M. Saleh 1, Abdelhady M. Shebl 2
Secondary malignancies following renal transplantation are not an uncommon event. In this report we considered one of the causes of posttransplant mortality. We report a renal transplant case and immune suppression treatment followed 11 years later by synchronous skin squamous cell carcinoma and papillary thyroid carcinoma that was diagnosed, presented and managed at the Oncology Center at Mansoura University.
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[TEXT] => <sup>1</sup> Городская больница №40, Сестрорецк, Санкт-Петербург, Россия<br>
<sup>2</sup> Институт трансляционной биомедицины, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия<br>
<sup>3</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский<br>
государственный медицинский университет, Санкт-Петербург, Россия
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2 Институт трансляционной биомедицины, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
3 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский
государственный медицинский университет, Санкт-Петербург, Россия
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База данных Всемирной организации здравоохранения (ВОЗ) Комитета по номенклатуре факторов <span style="text-align: justify;">системы HLA (база данных IPD-IMGT/HLA) на сен</span><span style="text-align: justify;">тябрь 2018 г. содержала информацию о нуклеотид</span><span style="text-align: justify;">ных последовательностях 20272 различных аллелей </span><span style="text-align: justify;">HLA, из которых 14800 были аллелями HLA класса I, </span><span style="text-align: justify;">а 5288 – класса II.</span>
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На протяжении последних 20 лет при секвенировании генома человека, животных, бактерий и вирусов преобладает автоматизированная технология Сэнгера. Однако необходимость более быстрого скрининга генома стимулировало развитие новых технологий мультиплексного секвенирования ДНК. Эти современные методы обозначаются как подходы следующего поколения (Next-Generation Sequencing, NGS).
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Целью нашего исследования было сравнение двух этих методов и оценка их эффективности. Чтобы достичь этой цели, мы выбрали группу из 35 образцов ДНК, в основном – потенциальных доноров гемопоэтических клеток, и провели сравнительный анализ по Сэнгеру и методом NGS. Метод NGS позволяет выявлять редкие или новые варианты аллелей. Этот подход подтвержден в качестве более чувствительного и более экономичного, особенно в больших лабораториях по HLA-типированию.
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<h2 style="text-align: justify;">Ключевые слова</h2>
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Главный комплекс гистосовместимости, новые аллели HLA, технологические решения, секвенирование следующего поколения, NGS, секвенирование по Сэнгеру, трансплантация гемопоэтических клеток, типирование по сиквенсам ДНК.
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База данных Всемирной организации здравоохранения (ВОЗ) Комитета по номенклатуре факторов системы HLA (база данных IPD-IMGT/HLA) на сентябрь 2018 г. содержала информацию о нуклеотидных последовательностях 20272 различных аллелей HLA, из которых 14800 были аллелями HLA класса I, а 5288 – класса II.
На протяжении последних 20 лет при секвенировании генома человека, животных, бактерий и вирусов преобладает автоматизированная технология Сэнгера. Однако необходимость более быстрого скрининга генома стимулировало развитие новых технологий мультиплексного секвенирования ДНК. Эти современные методы обозначаются как подходы следующего поколения (Next-Generation Sequencing, NGS).
Целью нашего исследования было сравнение двух этих методов и оценка их эффективности. Чтобы достичь этой цели, мы выбрали группу из 35 образцов ДНК, в основном – потенциальных доноров гемопоэтических клеток, и провели сравнительный анализ по Сэнгеру и методом NGS. Метод NGS позволяет выявлять редкие или новые варианты аллелей. Этот подход подтвержден в качестве более чувствительного и более экономичного, особенно в больших лабораториях по HLA-типированию.
Ключевые слова
Главный комплекс гистосовместимости, новые аллели HLA, технологические решения, секвенирование следующего поколения, NGS, секвенирование по Сэнгеру, трансплантация гемопоэтических клеток, типирование по сиквенсам ДНК.
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<sup>2</sup> Institute of Translation Biomedicine, St. Petersburg State University, St. Petersburg, Russia<br>
<sup>3</sup> Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia<br>
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2 Institute of Translation Biomedicine, St. Petersburg State University, St. Petersburg, Russia
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The database of the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System (IPD-IMGT/HLA Database) contained information on the nucleotide sequences of 20272 diff erent HLA alleles in September 2018, of which 14800 were HLA class I and 5288 were found for the HLA class II alleles. Over the last 20 years, the automated Sanger technique is a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening stimulated novel technologies of multiplex DNA sequencing. These modern methods are depicted as the second-generation approaches (Next-Generation Sequencing, NGS). The aim of our research was a comparison of two methods and their effi ciency evaluation. To achieve our purpose, we selected a group of 35 DNA samples, mainly from potential hematopoietic cells donors, and conducted a comparative analysis by Sanger and NGS method. NGS method allowed detecting rare or novel variants of alleles. This approach is confirmed to be more sensitive and more cost-eff ective, especially in large HLA-typing laboratories.
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<h2 style="text-align: justify;">Keywords</h2>
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Major histocompatibility complex, novel HLA alleles, technological solutions, next-generation sequencing, NGS, Sanger sequencing, hematopoietic cells transplantation, Sequence-Based Typing (SBT).
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Keywords
Major histocompatibility complex, novel HLA alleles, technological solutions, next-generation sequencing, NGS, Sanger sequencing, hematopoietic cells transplantation, Sequence-Based Typing (SBT).
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Oleg S. Glotov 1,2, Olga V. Romanova 1,2, Yuri A. Eismont 1, Andrey M. Sarana 1,2, Sergey G. Scherbak 1,2, Elena V. Kuzmich 3, Alexander L. Alyanskiy 3, Natalya E. Ivanova 3, Vera V. Teplyashina 3, Yury A. Serov 3, Ludmila S. Zubarovskaya 3, Boris V. Afanasyev 3
2 Institute of Translation Biomedicine, St. Petersburg State University, St. Petersburg, Russia
3 Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
The database of the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System (IPD-IMGT/HLA Database) contained information on the nucleotide sequences of 20272 diff erent HLA alleles in September 2018, of which 14800 were HLA class I and 5288 were found for the HLA class II alleles. Over the last 20 years, the automated Sanger technique is a prevalent approach to genome sequencing in humans, animals, bacteria, and viruses. However, a need for more rapid routine genome screening stimulated novel technologies of multiplex DNA sequencing. These modern methods are depicted as the second-generation approaches (Next-Generation Sequencing, NGS). The aim of our research was a comparison of two methods and their effi ciency evaluation. To achieve our purpose, we selected a group of 35 DNA samples, mainly from potential hematopoietic cells donors, and conducted a comparative analysis by Sanger and NGS method. NGS method allowed detecting rare or novel variants of alleles. This approach is confirmed to be more sensitive and more cost-eff ective, especially in large HLA-typing laboratories.
Keywords
Major histocompatibility complex, novel HLA alleles, technological solutions, next-generation sequencing, NGS, Sanger sequencing, hematopoietic cells transplantation, Sequence-Based Typing (SBT).
Experimental studies
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<sup>*</sup><sup>*</sup><sup>*</sup> Лаборатория патоморфологии НИЦ<br>
<sup>*</sup><sup>*</sup><sup>*</sup><sup>*</sup> Лаборатория инвазивных технологий НИЦ, ПСПбГМУ
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* Кафедра стоматологии профилактической
** Отдел биотехнологии Института детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой
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**** Лаборатория инвазивных технологий НИЦ, ПСПбГМУ
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[TEXT] => <sup>1</sup> Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова МЗ РФ (ПСПбГМУ), Санкт-Петербург, Россия<br>
<sup>2</sup> Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия<br>
<sup>3</sup> ФГБУ «Российский научный центр радиологии и хирургических технологий им. акад. А.М. Гранова» МЗ РФ, Санкт-Петербург, Россия
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2 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
3 ФГБУ «Российский научный центр радиологии и хирургических технологий им. акад. А.М. Гранова» МЗ РФ, Санкт-Петербург, Россия
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На сегодняшний день существует большое количество методов лечения воспалительных заболеваний пародонта, являющихся самыми распространенными стоматологическими заболеваниями в мире. Описывается метод хирургического лечения воспалительных заболеваний пародонта, приводится классификация природных и синтетических мембран, использующихся при хирургическом методе лечения, приводится новая технология с использованием природного полимера хитозана.
</p>
<h2 style="text-align: justify;">Материалы и методы</h2>
<p style="text-align: justify;">
Пористые трехмерные матрицы получали путем лиофилизации хитозана из 2% раствора уксусной кислоты. Полученные матрицы из хитозана содержали микропоры размером 100-150 нм. Эксперименты in vivo с пористыми хитозановыми мембранами проводили на кроликах. Животным наносили искусственные дефекты максиллярной кости и покрывали их испытуемым материалом. Некоторым животным наносили повреждение ребра, которое потом заполняли биодеградируемой матрицей из пористого хитозана.
</p>
<h2 style="text-align: justify;">Результаты</h2>
<p style="text-align: justify;">
Морфологическое исследование искусственно поврежденных ребер с имплантированным материалом выявило разнообразные изменения костной ткани и пористой матрицы без существенных признаков воспаления. Спустя 1 мес., на границе кости и матрицы отмечены остеокластическая реакция наряду с неоангиогенезом в зоне костного дефекта. Через 3-6 мес. после хирургического вмешательства образовались периостальные структуры, а также зоны локального фиброза
</p>
<h2 style="text-align: justify;">Выводы</h2>
<p style="text-align: justify;">
Пористые хитозановые матрицы оказались биосовместимым, биоинертным и биорезорбируемым материалом, что соответствует критериям, применимым к материалам для производства костных матриц.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Пародонт, регенерация, мембрана, хитозан.
</p>
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На сегодняшний день существует большое количество методов лечения воспалительных заболеваний пародонта, являющихся самыми распространенными стоматологическими заболеваниями в мире. Описывается метод хирургического лечения воспалительных заболеваний пародонта, приводится классификация природных и синтетических мембран, использующихся при хирургическом методе лечения, приводится новая технология с использованием природного полимера хитозана.
Материалы и методы
Пористые трехмерные матрицы получали путем лиофилизации хитозана из 2% раствора уксусной кислоты. Полученные матрицы из хитозана содержали микропоры размером 100-150 нм. Эксперименты in vivo с пористыми хитозановыми мембранами проводили на кроликах. Животным наносили искусственные дефекты максиллярной кости и покрывали их испытуемым материалом. Некоторым животным наносили повреждение ребра, которое потом заполняли биодеградируемой матрицей из пористого хитозана.
Результаты
Морфологическое исследование искусственно поврежденных ребер с имплантированным материалом выявило разнообразные изменения костной ткани и пористой матрицы без существенных признаков воспаления. Спустя 1 мес., на границе кости и матрицы отмечены остеокластическая реакция наряду с неоангиогенезом в зоне костного дефекта. Через 3-6 мес. после хирургического вмешательства образовались периостальные структуры, а также зоны локального фиброза
Выводы
Пористые хитозановые матрицы оказались биосовместимым, биоинертным и биорезорбируемым материалом, что соответствует критериям, применимым к материалам для производства костных матриц.
Ключевые слова
Пародонт, регенерация, мембрана, хитозан.
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A variety of medications is applied nowadays for treatment of infl ammatory periodontal diseases (IPD) which are the prevalent dental disorders worldwide. A method of surgical treatment is described for IPD. We present a classifi cation of natural and synthetic membranes used in surgical interventions, and describe a novel treatment technology using a natural chitosan polymer.
</p>
<h2 style="text-align: justify;">Materials and methods</h2>
<p style="text-align: justify;">
Porous 3-D matrices were obtained by lyophilization of chitosan solution from the 2% solution of acetic acid. Th e resulting chitosan matrices had micropores of 100 to 150 nm in size. Th e in vivo experiments with porous chitosan membranes were performed in rabbits. Artificial maxillar bone defects were infl icted, being overlaidby the tested material. Some animals were subjected to rib exposure and infl iction of a bone defect, then filled with a biodegradable porous chitosan-based matrix.
</p>
<h2 style="text-align: justify;">Results</h2>
<p style="text-align: justify;">
Morphological examination of artifi cially damaged ribs with implanted material has revealed various changes of bone tissue and porous matrix, without suffi cient inflammation signs. At 1 month, the matrix/bone border has shown osteoclasts at the site of bone defect 30 days aft er surgery, along with neoangiogenesis at the site of repair. At 3 to 6 months post-surgery, periosteal structures were organized, as well as local fi brosis was developed.
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<h2 style="text-align: justify;">Conclusion</h2>
<p style="text-align: justify;">
Porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Periodontium, regeneration, membrane, chitosan.
</p>
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A variety of medications is applied nowadays for treatment of infl ammatory periodontal diseases (IPD) which are the prevalent dental disorders worldwide. A method of surgical treatment is described for IPD. We present a classifi cation of natural and synthetic membranes used in surgical interventions, and describe a novel treatment technology using a natural chitosan polymer.
Materials and methods
Porous 3-D matrices were obtained by lyophilization of chitosan solution from the 2% solution of acetic acid. Th e resulting chitosan matrices had micropores of 100 to 150 nm in size. Th e in vivo experiments with porous chitosan membranes were performed in rabbits. Artificial maxillar bone defects were infl icted, being overlaidby the tested material. Some animals were subjected to rib exposure and infl iction of a bone defect, then filled with a biodegradable porous chitosan-based matrix.
Results
Morphological examination of artifi cially damaged ribs with implanted material has revealed various changes of bone tissue and porous matrix, without suffi cient inflammation signs. At 1 month, the matrix/bone border has shown osteoclasts at the site of bone defect 30 days aft er surgery, along with neoangiogenesis at the site of repair. At 3 to 6 months post-surgery, periosteal structures were organized, as well as local fi brosis was developed.
Conclusion
Porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices.
Keywords
Periodontium, regeneration, membrane, chitosan.
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Sergey B. Ulitovskiy 1*, Anna V. Antipova 1*, Alexander D. Vilesov 1**, 2, GalinaYu. Yukina 1***, Dmitry N. Suslov 1****, 3, Pavel V. Popryadukhin 1****, 2, Oleg V. Galibin 1**
1* Department of Preventive Stomatology
1** Biotechnology Department, R.Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation
1*** Laboratory of Pathomorphology, Th e University Research Center
1**** Laboratory of Invasive Technologies, Th e University Research Center
2 Institute of Macromolecular Compounds, Russian Academy of Sciences
3 Russian Research A.Granov Center of Radiology and Surgical Technologies, St. Petersburg, Russia
A variety of medications is applied nowadays for treatment of infl ammatory periodontal diseases (IPD) which are the prevalent dental disorders worldwide. A method of surgical treatment is described for IPD. We present a classifi cation of natural and synthetic membranes used in surgical interventions, and describe a novel treatment technology using a natural chitosan polymer.
Materials and methods
Porous 3-D matrices were obtained by lyophilization of chitosan solution from the 2% solution of acetic acid. Th e resulting chitosan matrices had micropores of 100 to 150 nm in size. Th e in vivo experiments with porous chitosan membranes were performed in rabbits. Artificial maxillar bone defects were infl icted, being overlaidby the tested material. Some animals were subjected to rib exposure and infl iction of a bone defect, then filled with a biodegradable porous chitosan-based matrix.
Results
Morphological examination of artifi cially damaged ribs with implanted material has revealed various changes of bone tissue and porous matrix, without suffi cient inflammation signs. At 1 month, the matrix/bone border has shown osteoclasts at the site of bone defect 30 days aft er surgery, along with neoangiogenesis at the site of repair. At 3 to 6 months post-surgery, periosteal structures were organized, as well as local fi brosis was developed.
Conclusion
Porous chitosan matrix proved to be biocompatible, bioinert, and bioresorbable material, thus meeting the requirements applicable to the materials suitable for production of the bone matrices.
Keywords
Periodontium, regeneration, membrane, chitosan.
Experimental studies
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[TEXT] => Лаборатория патоморфологии научно-исследовательского центра, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Российская Федерация<br>
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Эритропоэтин (ЭПО) является физиологическим стимулятором эритропоэза. Одним из основных эффектов ЭПО является снижение частоты апоптоза эритроидных клеток-предшественниц в костном мозге. Эти свойства ЭПО широко применяются при лечении различных заболеваний системы крови, в том числе – после трансплантации стволовых клеток. Ранее было установлено, что ЭПО оказывает активирующее воздействие на Т-лимфоциты (ТЛЦ), сопровождающееся увеличением количества флуоресцирующих митохондрий в клетке (nm/c) и увеличением суммарного трансмембранного потенциала на плазматической (Δφp) и митохондриальных мембранах (Δφm). Однако остается неясным, какой именно мембранный потенциал реагирует на воздействие ЭПО: Δφm, или (и) Δφp. Для ответа на этот вопрос мы использовали специфические ингибиторы окислительного фосфорилирования. Цель настоящего исследования – оценка роли митохондриальных функций в воздействии ЭПО на лимфоциты тимуса.
</p>
<h2 style="text-align: justify;">Материалы и методы</h2>
<p style="text-align: justify;">
Исследовалось влияние ЭПО (“Eprex”, Cilag) на флуоресценцию ТЛЦ крыс in vitro после краткосрочной инкубации и воздействия несколькими ингибиторами: динитрофенолом (ДНФ) – ингибитором дыхательной цепи и разобщителем окислительного фосфорилирования; пентахлорфенолом (ПХФ) – разобщителем окислительного фосфорилирования; дициклогексилкарбодиимидом (ДЦКД) – ингибитором мембрансвязанной части АТФ-азы митохондриальной мембраны с помощью зонда DSM [4-(p-диметиламиностирилил)-1-метил пиридиний], определяющего трансмембранный градиент электрического поля. ТЛЦ выделяли из тимусов по стандартной методике. Окрашенные ДСМ клетки исследовали на люминесцентном микроскопе («Люмам – Р 8», ЛОМО, Россия) с использованием термостатированного столика. В каждом препарате измеряли флуоресценцию 50-70 клеток и рассчитывали среднюю интенсивность флуоресценции ТЛЦ (F̃). В каждой флуоресцирующей клетке подсчитывали nm/c. Статистическую обработку данных экспериментов проводили по коэффициенту корреляции рангов Спирмена.
</p>
<h2 style="text-align: justify;">Результаты и обсуждение</h2>
<p style="text-align: justify;">
В серии экспериментов с ТЛЦ зарегистрировано снижение nm/c и F̃ после инкубации со всеми использованными ингибиторами, причем степень и скорость снижения этих параметров зависела от типа ингибитора и длительности инкубации. Максимальное снижение энергетики ТЛЦ достигалось при инкубации с ДНФ, после которого ЭПО не восстанавливает F̃ и nm/c. После инкубации с ПХФ ЭПО восстанавливает ~20-23% nm/c и F̃. Реакция ТЛЦ на ДЦКД подтверждает важную роль АТФ-азы в поддержании мембранного митохондриального потенциала. После деэнергизации ТЛЦ под действием ДЦКД, ЭПО восстанавливает ~42% nm/c и ~38% F̃.
</p>
<h2 style="text-align: justify;">Заключение</h2>
<p style="text-align: justify;">
ЭПО способен частично восстанавливать поляризацию мембран митохондрий в ТЛЦ, нарушенную в результате воздействия ингибитора АТФ-азы (ДЦКД).
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
Эритропоэтин, Т-лимфоциты, энергетическая активность, ингибиторы, потенциалчувствительный витальный флуоресцентный зонд-катион 4-(п-диметиламиностирил)-1-метилпиридиния (ДСМ).
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Эритропоэтин (ЭПО) является физиологическим стимулятором эритропоэза. Одним из основных эффектов ЭПО является снижение частоты апоптоза эритроидных клеток-предшественниц в костном мозге. Эти свойства ЭПО широко применяются при лечении различных заболеваний системы крови, в том числе – после трансплантации стволовых клеток. Ранее было установлено, что ЭПО оказывает активирующее воздействие на Т-лимфоциты (ТЛЦ), сопровождающееся увеличением количества флуоресцирующих митохондрий в клетке (nm/c) и увеличением суммарного трансмембранного потенциала на плазматической (Δφp) и митохондриальных мембранах (Δφm). Однако остается неясным, какой именно мембранный потенциал реагирует на воздействие ЭПО: Δφm, или (и) Δφp. Для ответа на этот вопрос мы использовали специфические ингибиторы окислительного фосфорилирования. Цель настоящего исследования – оценка роли митохондриальных функций в воздействии ЭПО на лимфоциты тимуса.
Материалы и методы
Исследовалось влияние ЭПО (“Eprex”, Cilag) на флуоресценцию ТЛЦ крыс in vitro после краткосрочной инкубации и воздействия несколькими ингибиторами: динитрофенолом (ДНФ) – ингибитором дыхательной цепи и разобщителем окислительного фосфорилирования; пентахлорфенолом (ПХФ) – разобщителем окислительного фосфорилирования; дициклогексилкарбодиимидом (ДЦКД) – ингибитором мембрансвязанной части АТФ-азы митохондриальной мембраны с помощью зонда DSM [4-(p-диметиламиностирилил)-1-метил пиридиний], определяющего трансмембранный градиент электрического поля. ТЛЦ выделяли из тимусов по стандартной методике. Окрашенные ДСМ клетки исследовали на люминесцентном микроскопе («Люмам – Р 8», ЛОМО, Россия) с использованием термостатированного столика. В каждом препарате измеряли флуоресценцию 50-70 клеток и рассчитывали среднюю интенсивность флуоресценции ТЛЦ (F̃). В каждой флуоресцирующей клетке подсчитывали nm/c. Статистическую обработку данных экспериментов проводили по коэффициенту корреляции рангов Спирмена.
Результаты и обсуждение
В серии экспериментов с ТЛЦ зарегистрировано снижение nm/c и F̃ после инкубации со всеми использованными ингибиторами, причем степень и скорость снижения этих параметров зависела от типа ингибитора и длительности инкубации. Максимальное снижение энергетики ТЛЦ достигалось при инкубации с ДНФ, после которого ЭПО не восстанавливает F̃ и nm/c. После инкубации с ПХФ ЭПО восстанавливает ~20-23% nm/c и F̃. Реакция ТЛЦ на ДЦКД подтверждает важную роль АТФ-азы в поддержании мембранного митохондриального потенциала. После деэнергизации ТЛЦ под действием ДЦКД, ЭПО восстанавливает ~42% nm/c и ~38% F̃.
Заключение
ЭПО способен частично восстанавливать поляризацию мембран митохондрий в ТЛЦ, нарушенную в результате воздействия ингибитора АТФ-азы (ДЦКД).
Ключевые слова
Эритропоэтин, Т-лимфоциты, энергетическая активность, ингибиторы, потенциалчувствительный витальный флуоресцентный зонд-катион 4-(п-диметиламиностирил)-1-метилпиридиния (ДСМ).
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Erythropoietin (EPO) is a physiological stimulator of erythropoiesis. One of the main eff ects of EPO is to prevent apoptosis of erythroid progenitor cells in the bone marrow. Th ese properties of EPO are widely used for treatment of various hematopoietic disorders including posttransplant conditions. Previously, it was found that activating EPO-eff ect on T-lymphocytes (TLC) accompanied by an increase in the number of fluorescent mitochondria (n m/c) and an increase in the total transmembrane potential on plasmatic (Δφp) and mitochondrial membranes (Δφm). However, it remains unclear which membrane potential is responsible for the EPO effect. Hence, we used specifi c inhibitors of oxidative phosphorylation in the respiratory chain. The aim of the present work was to assess the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes.
</p>
<p style="text-align: justify;">
<span style="font-family: Cuprum, sans-serif; font-size: 26px;">Materials and methods</span>
</p>
<p style="text-align: justify;">
We studied EPO (Eprex, Cilag) infl uence on fl uorescence of rat TLC aft er short-term incubation and treatment with some inhibitors: dinitrophenol (DNP-uncoupler of oxidative phosphorylation and inhibitor of respiratory chain), pentachlorphenol (PCP- uncoupler of oxidative phosphorylation), N,N -dicyclohexylcarbodiimide (DCCD- inhibitor of Ca2+- dependent mitochondria ATP-аse). Th e cells were then tested by electrical fi eld gradient sensitive probe DSM [4-(p-dimethylaminostyryl)- 1-methylpyridinium]. Rat TLC were isolated according to the standard method. Th e microfl uorimetric studies of DSM-stained TLC were performed by means of fl uorescent microscope “Lumam R-8”, “LOMO”, Russia) with thermostatic plate. Fift y to 70 single cells were measured per each specimen the mean fl uorescence intensity of TLC was calculated (F̃), as well as nm/c values. Statistical evaluation of the data was performed by the Spearmen range correlation.
</p>
<h2 style="text-align: justify;">Results</h2>
<p style="text-align: justify;">
In a series of experiments with TLC, we have registered a decrease in F̃ and nm/c aft er incubation with all used inhibitors. It was found that the diff erence in decrease of nm/c rates and F̃ values depends on the type of inhibitor and on the duration of incubation. Maximal irreversible reduction of the TLC energy potential (F̃ and nm/c) after incubation was seen with DNP being not restored by EPO. Aft er incubation with PCP, EPO restores nm/c and F̃ by ca. 20-23%. Th e reaction of TLC on the DCCD confirms the important role of the ATP-ase for maintenance of mitochondrial membrane potential. After de-energization of TLC by DCCD, EPO has the maximum rescuing effect, i.e. recovery by approx. 42% for nm/c and ~38%<br>
for F̃ values.
</p>
<h2 style="text-align: justify;">Conclusion</h2>
<p style="text-align: justify;">
EPO is able to partially recover the damage and polarization of the mitochondria membranes in TLC disturbed aft er exposure to specifi c ATP-ase inhibitor (DCCD). This in vitro approach may be used for screening other growth factors.
</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">
Erythropoietin, T-lymphocytes, energy activity, inhibitors, electrical field gradient sensitive probe DSM [4-(p-dimethylaminostyryl)-1-methylpyridinium].
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Erythropoietin (EPO) is a physiological stimulator of erythropoiesis. One of the main eff ects of EPO is to prevent apoptosis of erythroid progenitor cells in the bone marrow. Th ese properties of EPO are widely used for treatment of various hematopoietic disorders including posttransplant conditions. Previously, it was found that activating EPO-eff ect on T-lymphocytes (TLC) accompanied by an increase in the number of fluorescent mitochondria (n m/c) and an increase in the total transmembrane potential on plasmatic (Δφp) and mitochondrial membranes (Δφm). However, it remains unclear which membrane potential is responsible for the EPO effect. Hence, we used specifi c inhibitors of oxidative phosphorylation in the respiratory chain. The aim of the present work was to assess the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes.
Materials and methods
We studied EPO (Eprex, Cilag) infl uence on fl uorescence of rat TLC aft er short-term incubation and treatment with some inhibitors: dinitrophenol (DNP-uncoupler of oxidative phosphorylation and inhibitor of respiratory chain), pentachlorphenol (PCP- uncoupler of oxidative phosphorylation), N,N -dicyclohexylcarbodiimide (DCCD- inhibitor of Ca2+- dependent mitochondria ATP-аse). Th e cells were then tested by electrical fi eld gradient sensitive probe DSM [4-(p-dimethylaminostyryl)- 1-methylpyridinium]. Rat TLC were isolated according to the standard method. Th e microfl uorimetric studies of DSM-stained TLC were performed by means of fl uorescent microscope “Lumam R-8”, “LOMO”, Russia) with thermostatic plate. Fift y to 70 single cells were measured per each specimen the mean fl uorescence intensity of TLC was calculated (F̃), as well as nm/c values. Statistical evaluation of the data was performed by the Spearmen range correlation.
Results
In a series of experiments with TLC, we have registered a decrease in F̃ and nm/c aft er incubation with all used inhibitors. It was found that the diff erence in decrease of nm/c rates and F̃ values depends on the type of inhibitor and on the duration of incubation. Maximal irreversible reduction of the TLC energy potential (F̃ and nm/c) after incubation was seen with DNP being not restored by EPO. Aft er incubation with PCP, EPO restores nm/c and F̃ by ca. 20-23%. Th e reaction of TLC on the DCCD confirms the important role of the ATP-ase for maintenance of mitochondrial membrane potential. After de-energization of TLC by DCCD, EPO has the maximum rescuing effect, i.e. recovery by approx. 42% for nm/c and ~38%
for F̃ values.
Conclusion
EPO is able to partially recover the damage and polarization of the mitochondria membranes in TLC disturbed aft er exposure to specifi c ATP-ase inhibitor (DCCD). This in vitro approach may be used for screening other growth factors.
Keywords
Erythropoietin, T-lymphocytes, energy activity, inhibitors, electrical field gradient sensitive probe DSM [4-(p-dimethylaminostyryl)-1-methylpyridinium].
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Tatyana V. Parkhomenko, Vladimir V. Tomson, Oleg V. Galibin
Erythropoietin (EPO) is a physiological stimulator of erythropoiesis. One of the main eff ects of EPO is to prevent apoptosis of erythroid progenitor cells in the bone marrow. Th ese properties of EPO are widely used for treatment of various hematopoietic disorders including posttransplant conditions. Previously, it was found that activating EPO-eff ect on T-lymphocytes (TLC) accompanied by an increase in the number of fluorescent mitochondria (n m/c) and an increase in the total transmembrane potential on plasmatic (Δφp) and mitochondrial membranes (Δφm). However, it remains unclear which membrane potential is responsible for the EPO effect. Hence, we used specifi c inhibitors of oxidative phosphorylation in the respiratory chain. The aim of the present work was to assess the role of mitochondrial functions in EPO eff ects upon thymic lymphocytes.
Materials and methods
We studied EPO (Eprex, Cilag) infl uence on fl uorescence of rat TLC aft er short-term incubation and treatment with some inhibitors: dinitrophenol (DNP-uncoupler of oxidative phosphorylation and inhibitor of respiratory chain), pentachlorphenol (PCP- uncoupler of oxidative phosphorylation), N,N -dicyclohexylcarbodiimide (DCCD- inhibitor of Ca2+- dependent mitochondria ATP-аse). Th e cells were then tested by electrical fi eld gradient sensitive probe DSM [4-(p-dimethylaminostyryl)- 1-methylpyridinium]. Rat TLC were isolated according to the standard method. Th e microfl uorimetric studies of DSM-stained TLC were performed by means of fl uorescent microscope “Lumam R-8”, “LOMO”, Russia) with thermostatic plate. Fift y to 70 single cells were measured per each specimen the mean fl uorescence intensity of TLC was calculated (F̃), as well as nm/c values. Statistical evaluation of the data was performed by the Spearmen range correlation.
Results
In a series of experiments with TLC, we have registered a decrease in F̃ and nm/c aft er incubation with all used inhibitors. It was found that the diff erence in decrease of nm/c rates and F̃ values depends on the type of inhibitor and on the duration of incubation. Maximal irreversible reduction of the TLC energy potential (F̃ and nm/c) after incubation was seen with DNP being not restored by EPO. Aft er incubation with PCP, EPO restores nm/c and F̃ by ca. 20-23%. Th e reaction of TLC on the DCCD confirms the important role of the ATP-ase for maintenance of mitochondrial membrane potential. After de-energization of TLC by DCCD, EPO has the maximum rescuing effect, i.e. recovery by approx. 42% for nm/c and ~38%
for F̃ values.
Conclusion
EPO is able to partially recover the damage and polarization of the mitochondria membranes in TLC disturbed aft er exposure to specifi c ATP-ase inhibitor (DCCD). This in vitro approach may be used for screening other growth factors.
Keywords
Erythropoietin, T-lymphocytes, energy activity, inhibitors, electrical field gradient sensitive probe DSM [4-(p-dimethylaminostyryl)-1-methylpyridinium].