Том 7, Номер 1

Изменить отображение страницы на: только анонсы

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Как известно, иммунотерапия является ключевым компонентом системной противоопухолевой терапии, наряду с лучевой и химиотерапией. Она представляется эффективным средством эрадикации опухолевых клеток, оставшихся после обычной циторедуктивной терапии. Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является одним из видов адоптивной иммунотерапии, которая все чаще применяется для лечения различных системных и солидных новообразований. Однако, несмотря на относительную эффективность алло-ТГСК, резистентность злокачественных клеток остается критической проблемой, даже после такого терапевтического вмешательства. Поэтому иммунотерапия может проводиться как до ТГСК, так и после нее. За последнее время появилось значительное число новых средств лечения, что позволяет создать «мостик» для последующей алло-ТГСК, как, например, введение моноклональных антител против антигенов CD20 или CD30, в том числе – их конъюгатов с цитотоксическими агентами. Другая группа препаратов включает биспецифические моноклональные антитела, как, например, недавно зарегистрированный блинатумомаб (антитело к CD3/CD19), который индуцирует Т-клеточный ответ на бласты В-клеточного ростка. Далее, наиболее перспективной группой новых препаратов являются ингибиторы контрольных точек апоптоза, например – антитела к PD1. Свежие клинические и экспериментальные данные указывают на то, что эта группа лекарственных средств может применяться в качестве монотерапии или в сочетании с другими воздействиями при самых различных рефрактерных злокачественных новообразованиях. Повышение эффективности лечения ингибиторами PD-1 может быть достигнуто при оптимальном сочетании цитостатической терапии и иммуномодулирующих препаратов, как, например, леналидомида и других веществ. Их нынешнее применение в схемах монотерапии, в том числе при болезни Ходжкина, не ведет к высокой частоте полного излечения, хотя инициальная частота клинического ответа довольно высока. Эти эффекты препаратов-ингибиторов контрольных точек свидетельствуют об их особой перспективности для промежуточной (“bridging”) терапии, хотя необходимо еще уточнить оптимальную дозировку препарата, а также период времени для проведения последующей алло-ТГСК. Разработка оптимальных сочетаний новых иммунотерапевтических агентов с ранее известными методами, включая химиотерапию и трансплантацию стволовых клеток, приобретают сейчас первостепенное значение, как в фундаментальных, так и клинических ситуациях.Несомненно, имеется большое число пациентов, в том числе с ВИЧ-инфекцией, которым эти исследования принесут пользу. Мы будем рады, если наши русско- и англоязычные авторы сочтут возможной подачу своих оригинальных и обзорных статей в журнал «Клеточная Терапия и Трансплантация» (СТТ). Публикация на английском языке (с расширенным русским резюме) результатов, полученных молодыми специалистами, поможет им, в частности, адаптироваться к западным стандартам публикаций и приобрести дополнительный опыт в отправке научных статей. 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Как известно, иммунотерапия является ключевым компонентом системной противоопухолевой терапии, наряду с лучевой и химиотерапией. Она представляется эффективным средством эрадикации опухолевых клеток, оставшихся после обычной циторедуктивной терапии. Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является одним из видов адоптивной иммунотерапии, которая все чаще применяется для лечения различных системных и солидных новообразований. Однако, несмотря на относительную эффективность алло-ТГСК, резистентность злокачественных клеток остается критической проблемой, даже после такого терапевтического вмешательства. Поэтому иммунотерапия может проводиться как до ТГСК, так и после нее. За последнее время появилось значительное число новых средств лечения, что позволяет создать «мостик» для последующей алло-ТГСК, как, например, введение моноклональных антител против антигенов CD20 или CD30, в том числе – их конъюгатов с цитотоксическими агентами. Другая группа препаратов включает биспецифические моноклональные антитела, как, например, недавно зарегистрированный блинатумомаб (антитело к CD3/CD19), который индуцирует Т-клеточный ответ на бласты В-клеточного ростка. Далее, наиболее перспективной группой новых препаратов являются ингибиторы контрольных точек апоптоза, например – антитела к PD1. Свежие клинические и экспериментальные данные указывают на то, что эта группа лекарственных средств может применяться в качестве монотерапии или в сочетании с другими воздействиями при самых различных рефрактерных злокачественных новообразованиях. Повышение эффективности лечения ингибиторами PD-1 может быть достигнуто при оптимальном сочетании цитостатической терапии и иммуномодулирующих препаратов, как, например, леналидомида и других веществ. Их нынешнее применение в схемах монотерапии, в том числе при болезни Ходжкина, не ведет к высокой частоте полного излечения, хотя инициальная частота клинического ответа довольно высока. Эти эффекты препаратов-ингибиторов контрольных точек свидетельствуют об их особой перспективности для промежуточной (“bridging”) терапии, хотя необходимо еще уточнить оптимальную дозировку препарата, а также период времени для проведения последующей алло-ТГСК. Разработка оптимальных сочетаний новых иммунотерапевтических агентов с ранее известными методами, включая химиотерапию и трансплантацию стволовых клеток, приобретают сейчас первостепенное значение, как в фундаментальных, так и клинических ситуациях.Несомненно, имеется большое число пациентов, в том числе с ВИЧ-инфекцией, которым эти исследования принесут пользу. Мы будем рады, если наши русско- и англоязычные авторы сочтут возможной подачу своих оригинальных и обзорных статей в журнал «Клеточная Терапия и Трансплантация» (СТТ). Публикация на английском языке (с расширенным русским резюме) результатов, полученных молодыми специалистами, поможет им, в частности, адаптироваться к западным стандартам публикаций и приобрести дополнительный опыт в отправке научных статей. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5875) "

Уважаемые авторы и читатели журнала СТТ!

Как известно, иммунотерапия является ключевым компонентом системной противоопухолевой терапии, наряду с лучевой и химиотерапией. Она представляется эффективным средством эрадикации опухолевых клеток, оставшихся после обычной циторедуктивной терапии. Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является одним из видов адоптивной иммунотерапии, которая все чаще применяется для лечения различных системных и солидных новообразований.

Однако, несмотря на относительную эффективность алло-ТГСК, резистентность злокачественных клеток остается критической проблемой, даже после такого терапевтического вмешательства. Поэтому иммунотерапия может проводиться как до ТГСК, так и после нее. За последнее время появилось значительное число новых средств лечения, что позволяет создать «мостик» для последующей алло-ТГСК, как, например, введение моноклональных антител против антигенов CD20 или CD30, в том числе – их конъюгатов с цитотоксическими агентами. Другая группа препаратов включает биспецифические моноклональные антитела, как, например, недавно зарегистрированный блинатумомаб (антитело к CD3/CD19), который индуцирует Т-клеточный ответ на бласты В-клеточного ростка.

Далее, наиболее перспективной группой новых препаратов являются ингибиторы контрольных точек апоптоза, например – антитела к PD1. Свежие клинические и экспериментальные данные указывают на то, что эта группа лекарственных средств может применяться в качестве монотерапии или в сочетании с другими воздействиями при самых различных рефрактерных злокачественных новообразованиях. Повышение эффективности лечения ингибиторами PD-1 может быть достигнуто при оптимальном сочетании цитостатической терапии и иммуномодулирующих препаратов, как, например, леналидомида и других веществ. Их нынешнее применение в схемах монотерапии, в том числе при болезни Ходжкина, не ведет к высокой частоте полного излечения, хотя инициальная частота клинического ответа довольно высока. Эти эффекты препаратов-ингибиторов контрольных точек свидетельствуют об их особой перспективности для промежуточной (“bridging”) терапии, хотя необходимо еще уточнить оптимальную дозировку препарата, а также период времени для проведения последующей алло-ТГСК.

Разработка оптимальных сочетаний новых иммунотерапевтических агентов с ранее известными методами, включая химиотерапию и трансплантацию стволовых клеток, приобретают сейчас первостепенное значение, как в фундаментальных, так и клинических ситуациях.Несомненно, имеется большое число пациентов, в том числе с ВИЧ-инфекцией, которым эти исследования принесут пользу.

Мы будем рады, если наши русско- и англоязычные авторы сочтут возможной подачу своих оригинальных и обзорных статей в журнал «Клеточная Терапия и Трансплантация» (СТТ). Публикация на английском языке (с расширенным русским резюме) результатов, полученных молодыми специалистами, поможет им, в частности, адаптироваться к западным стандартам публикаций и приобрести дополнительный опыт в отправке научных статей.

Dear CTT authors and readers,

Immunotherapy is known to be a crucial component of systemic anticancer therapy, along with radiation and chemotherapy. It seems to be an effective means to eradicate residual tumor cells that escape conventional cytoreductive chemotherapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a kind of adoptive immune therapy applied at increasing rates for treatment of different systemic and solid malignancies.

However, despite relative efficiency of allo-HSCT, the malignant cell resistance remains the critical issue even after this intervention. Therefore, immune therapy could be performed both before and after HSCT. A substantial number of novel treatments has emerged recently which provide a “bridge” for subsequent allo-HSCT, e.g., monoclonal antibodies against CD20 or CD30 antigens, including conjugates with cytotoxic agents. The other group includes bispecific monoclonal antibodies, like recently registered CD3/CD19 blinatumomab, which induce T cell response to the blast cells of B lineage.

Furthermore, the most promising group of novel drugs is checkpoint inhibitors, for example, anti-PD1 antibodies. Growing clinical and experimental data indicate that this group of drugs might have a role as monotherapy or in combination with other interventions in a broad spectrum of refractory malignancies. Higher efficiency of the PD-1 inhibitorsmay be achieved by optimal combining cytostatic chemotherapy and immunomodulatory drugs, e.g., lenalidomide and other agents. Their current application as monotherapy, like in Hodgkin’s disease, is not associated with high proportion of cured patients, although the initial clinical response rate is rather high. These aspects of checkpoint inhibitors make them one of the most promising “bridging” therapies, but the optimal drug dosing as well as proper timing of subsequent allo-HSCT are still to be elucidated.

The research in the field of optimal combination of novel immunotherapeutic agents and well-known approaches, including chemotherapy and stem cell transplantation, is among current priorities, both in the fundamental and clinical settings. There is definitely a large number of patients, including those with HIV infection, who will benefit from these upcoming studies.

We would be happy if our English- and Russian-speaking readers will be able to submit their original or review articles to the Cellular Therapy and Transplantation Journal. Publication in English (with extended Russian abstracts) of the data obtained by young specialists will help them to adapt for Western publication standards and to gain further experience in the research paper submission.

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["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) "20081" ["VALUE"]=> array(2) { ["TEXT"]=> string(3083) " Dear CTT authors and readers, Immunotherapy is known to be a crucial component of systemic anticancer therapy, along with radiation and chemotherapy. It seems to be an effective means to eradicate residual tumor cells that escape conventional cytoreductive chemotherapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a kind of adoptive immune therapy applied at increasing rates for treatment of different systemic and solid malignancies. However, despite relative efficiency of allo-HSCT, the malignant cell resistance remains the critical issue even after this intervention. Therefore, immune therapy could be performed both before and after HSCT. A substantial number of novel treatments has emerged recently which provide a “bridge” for subsequent allo-HSCT, e.g., monoclonal antibodies against CD20 or CD30 antigens, including conjugates with cytotoxic agents. The other group includes bispecific monoclonal antibodies, like recently registered CD3/CD19 blinatumomab, which induce T cell response to the blast cells of B lineage. Furthermore, the most promising group of novel drugs is checkpoint inhibitors, for example, anti-PD1 antibodies. Growing clinical and experimental data indicate that this group of drugs might have a role as monotherapy or in combination with other interventions in a broad spectrum of refractory malignancies. Higher efficiency of the PD-1 inhibitorsmay be achieved by optimal combining cytostatic chemotherapy and immunomodulatory drugs, e.g., lenalidomide and other agents. Their current application as monotherapy, like in Hodgkin’s disease, is not associated with high proportion of cured patients, although the initial clinical response rate is rather high. These aspects of checkpoint inhibitors make them one of the most promising “bridging” therapies, but the optimal drug dosing as well as proper timing of subsequent allo-HSCT are still to be elucidated. The research in the field of optimal combination of novel immunotherapeutic agents and well-known approaches, including chemotherapy and stem cell transplantation, is among current priorities, both in the fundamental and clinical settings. There is definitely a large number of patients, including those with HIV infection, who will benefit from these upcoming studies. We would be happy if our English- and Russian-speaking readers will be able to submit their original or review articles to the Cellular Therapy and Transplantation Journal. Publication in English (with extended Russian abstracts) of the data obtained by young specialists will help them to adapt for Western publication standards and to gain further experience in the research paper submission. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2951) "

Dear CTT authors and readers,

" } ["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) "20082" ["VALUE"]=> string(17) "Editorial article" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(17) "Editorial article" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(17) "Editorial article" } ["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) "20078" ["VALUE"]=> array(2) { ["TEXT"]=> string(52) "Профессор Борис В. Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(52) "Профессор 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" } ["DISPLAY_VALUE"]=> string(52) "Профессор 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) "20079" ["VALUE"]=> array(2) { ["TEXT"]=> string(6007) " Уважаемые авторы и читатели журнала СТТ! Как известно, иммунотерапия является ключевым компонентом системной противоопухолевой терапии, наряду с лучевой и химиотерапией. Она представляется эффективным средством эрадикации опухолевых клеток, оставшихся после обычной циторедуктивной терапии. Аллогенная трансплантация гемопоэтических стволовых клеток (алло-ТГСК) является одним из видов адоптивной иммунотерапии, которая все чаще применяется для лечения различных системных и солидных новообразований. Однако, несмотря на относительную эффективность алло-ТГСК, резистентность злокачественных клеток остается критической проблемой, даже после такого терапевтического вмешательства. Поэтому иммунотерапия может проводиться как до ТГСК, так и после нее. За последнее время появилось значительное число новых средств лечения, что позволяет создать «мостик» для последующей алло-ТГСК, как, например, введение моноклональных антител против антигенов CD20 или CD30, в том числе – их конъюгатов с цитотоксическими агентами. Другая группа препаратов включает биспецифические моноклональные антитела, как, например, недавно зарегистрированный блинатумомаб (антитело к CD3/CD19), который индуцирует Т-клеточный ответ на бласты В-клеточного ростка. Далее, наиболее перспективной группой новых препаратов являются ингибиторы контрольных точек апоптоза, например – антитела к PD1. Свежие клинические и экспериментальные данные указывают на то, что эта группа лекарственных средств может применяться в качестве монотерапии или в сочетании с другими воздействиями при самых различных рефрактерных злокачественных новообразованиях. Повышение эффективности лечения ингибиторами PD-1 может быть достигнуто при оптимальном сочетании цитостатической терапии и иммуномодулирующих препаратов, как, например, леналидомида и других веществ. Их нынешнее применение в схемах монотерапии, в том числе при болезни Ходжкина, не ведет к высокой частоте полного излечения, хотя инициальная частота клинического ответа довольно высока. Эти эффекты препаратов-ингибиторов контрольных точек свидетельствуют об их особой перспективности для промежуточной (“bridging”) терапии, хотя необходимо еще уточнить оптимальную дозировку препарата, а также период времени для проведения последующей алло-ТГСК. Разработка оптимальных сочетаний новых иммунотерапевтических агентов с ранее известными методами, включая химиотерапию и трансплантацию стволовых клеток, приобретают сейчас первостепенное значение, как в фундаментальных, так и клинических ситуациях.Несомненно, имеется большое число пациентов, в том числе с ВИЧ-инфекцией, которым эти исследования принесут пользу. Мы будем рады, если наши русско- и англоязычные авторы сочтут возможной подачу своих оригинальных и обзорных статей в журнал «Клеточная Терапия и Трансплантация» (СТТ). Публикация на английском языке (с расширенным русским резюме) результатов, полученных молодыми специалистами, поможет им, в частности, адаптироваться к западным стандартам публикаций и приобрести дополнительный опыт в отправке научных статей. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5875) "

Уважаемые авторы и читатели журнала СТТ!

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Introduction

Bone tissue engineering aims to restore tissues damaged due to a trauma, diseases, or congenital abnormalities [1]. The regeneration of facial skeletal tissues must consider ways to ensure the recovery of aesthetic characteristics. Additionally, the bone reconstruction should keep sufficient mechanical strength to protect internal organs and support movements enabling normal speech and masticatory functions [2].
Tissue engineering is a multidisciplinary field focused on the development of materials and strategies by merging the principles, methods and knowledge of chemistry, physics, engineering and biology [3]. This approach involves three fundamental elements: cells, scaffolds, and cell signaling, which are vital for eliciting the essential response from a designed tissue-engineered system [4]. The principles of tissue engineering have found widespread application in several branches of dentistry, such as periodontics, oral maxillofacial surgery, and implant dentistry. In implantology the most frequently observed problems are the lack of adequate bone tissue, proximity to important anatomical structures (such as the maxillary sinus and the inferior alveolar nerve) at the implantation site [5]. Multiple approaches to the treatment and restoration of craniofacial bone defects exist where tissue autografting and allografting are considered the best options [6]. However, these strategies are associated with intrinsic drawbacks, including limited availability of autologous grafts, and potential immunogenic rejection when attempting allogeneic grafting. Tissue engineering has been found to be a clinically relevant approach aiming for the promotion of tissue regeneration in craniofacial regions [7].
Tissue regeneration is a process which takes place after an acute injury, and it can be achieved by the restoration or repair of tissue structure. Formally speaking, the term regeneration refers to the complete reconstitution of lost or damaged tissue, whereas repair means restoration of some original structure followed by scar formation [8]. Relative contribution of regeneration and scarring of the tissue repairs depends on ability of the specialized tissue to regenerate, and on the extent of injury. A promising approach is to induce tissue regeneration at the defective site by introducing a solid scaffold acting as artificial extracellular matrix (ECM) [9]. Its surface promotes cell attachment, their subsequent proliferation and differentiation. Biocompatibility of artificial ECM is of great importance, since the surrounding cells find a favorable microenvironment for their homing and proliferation within such a scaffold. It can be implanted into the body as a cell-free scaffold, or it may be already supplied with cells and/or growth factors, cytokines, and genetic material (bioengineered scaffolds). The latter has the advantage by promoting faster tissue regeneration, especially in some pathological conditions, when the tissue does not have inherent self-regenerating potential [10].
To overcome the drawbacks of particulate bone graft materials, the three-dimensional (3D) porous biodegradable scaffolds have been introduced to dentistry clinics [11]. 3D porous scaffolds can maintain the physical space necessary for bone regeneration, thus not only preventing invasion of undesired cells but also anchoring endogenous osteogenic cells to induce cell in-growth and providing molecular environment for osteoblastic differentiation. The fabrication of an ideal personalized scaffold of precise shape and size has recently become possible with 3D bioprinting systems (3DPs) [12]. Synthetic polymers, such as polycaprolactone (PCL), are commonly used for the scaffold fabrication, because of their thermoplastic characteristics and suitable layer- by-layer processing of scaffolds by means of 3DPs [13]. In addition, PCL is a safe FDA-approved material for use in drug delivery devices and implantation scaffolds. Due to its biocompatibility and biodegradability, the PCL material can be employed as a bone substitute to reconstruct alveolar bones in the oral cavity [14].
Along with growth-promoting proteins, genes, and other stimulatory factors, common antibiotics and anti-inflammatory drugs are of utmost importance for successful tissue regeneration [15]. Antibiotic administration is fundamental to reduce infection risks during the implantation procedure and healing process, or to treat pre-existing infections. Anti-inflammatory drugs reduce inflammation at the site of scaffold implantation, thus promoting the healing of damaged tissue [16].
Extensive literature available on this topic highlights, how the most studied and suitable strategy involves the incorporation of drugs into scaffolds, or their encapsulation into polymeric drug-delivery systems that can be combined with the scaffold. In these terms, biodegradable polymers are potentially interesting and widely studied materials.
After a brief introduction, the following sections are dedicated to clarify the characteristics of scaffolds for bone regeneration and implantation in the maxillofacial region.

Structure of the craniofacial bone tissues

Orofacial structures are very unique in their development and function. Craniomaxillofacial bones consist of cranial and facial bones. Cranial bones enclose the brain and function mostly to protect it, whereas different facial bones such as the maxillary and mandible act as load-bearing bones for the dental region [17]. Bone consists of collagen fibers which are mineralized by hydroxyapatite (HA) to give a crystal structure and thus to provide mechanical strength. Osteoblasts differentiated from the bone marrow-derived mesenchymal stem cells (BMMSCs) regulate osteoid secretion and bone mineralization. Before osteoid mineralization, 94% of the osteoid is collagen fiber [18]. When the bone develops, osteoid is mineralized by calcium apatite to form a HA-like structure. Once the mineralization is complete, the calcified bone is composed of 25% organic matrix, 70% mineral and 5% water [18]. Bones are highly vascularized to provide nutrients and oxygen to the bone cells and to remove debris in the extracellular matrix. Other than osteoblasts, osteocytes and osteoclasts also facilitate bone regeneration and remodeling. In general, orofacial tissues have limited and variable capacity for regeneration [19].

Artificial scaffolds for bone tissue regeneration

A scaffold for tissue regeneration is a structure which is able to support and/or promote tissue regeneration. It should possess a 3D and well-defined macro-architecture and micro-architecture with an interconnected pore network [20].
Bone tissue presents anisotropic behavior because its strength depends on orientation of the applied load and resistance to high pressure/loadings, and the resistance depends on the positioning of bone in the human body and its size. For these reasons, specific scaffold structure, shape, and composition may be useful, according to the bone restoring needs. All these variables (shape, structure, and composition) should be balanced in order to find the combination that perfectly matches with the properties and functions of the damaged bone. This means a significant number of combinations among polymers, minerals, and other materials need to be evaluated [10].
Critical issues related to allograft and autograft implants are identified as high risk of infections, painful procedures needed to harvest bone graft from the iliac crests, and longpost-operative recovery [21]. In addition, autograft and allograft implants are made of avascular and non-viable tissue; they do not carry cellular components of bones, resulting in a lack of bone remodeling. The rates of failure for these procedures are up to 25-35%, due to graft rejection induced by the host immune system [22].
Even though metals are not biodegradable materials and do not promote bone tissue regeneration, they are widely used in implants for bone healing, and are worth mentioning. The main advantages of metallic implants are stiffness and high load-bearing mechanical properties combined with an absence of body immune response [23]. For these reasons, they are used frequently in bone surgery for tissue restoration. The mostly used metals are titanium and its alloys, and stainless steel; they seem to be useful, but require invasive procedures for implantation [24]. Classic metal implants do not promote osteoinduction or osteoconduction, and they do not improve bone regrowth. The metal implants are often withdrawn when bone healing is completed, implicating a second surgery associated with pain, high risk of infection, and further days of immobilization. Problems associated with stress shielding, fatigue, and loosening of implant are often noted with metal implants, leading to a second substitution surgery [25].
Biomaterials – namely biocompatible polymers, ceramic and bioglass – have the advantages that they integrate into the surrounding tissue without being rejected and minimize host reactions at the implant site [26]. This is an important property noted by many authors. Materials with these characteristics seem to accelerate tissue healing, and, moreover, an explant surgical procedure is not required when polymeric scaffolds are used, as the biomaterial is reabsorbed, or completely integrated with new tissue.
Scaffolds for bone regeneration can be made of diverse materials: polymers or polymers combined with calcium phosphate minerals as hydroxyapatite, or to other compounds, such as single-walled or multi-walled-carbon nanotubes [27]. They should meet all requirements of injectable products, such as sterility and apyrogenicity, because they are intended for implantation into the human body. Biocompatibility is an unavoidable requirement of the product: if it is a temporary scaffold, it should be biocompatible and bio-reabsorbable with controlled degradation and resorption rate. They can also provide a controlled release of specific bioactive factors in order to enhance or guide the regeneration events [28].
In the course of tissue regeneration, a biocompatible scaffold will allow cell adhesion and induce cell proliferation and differentiation without triggering inflammatory responses or immune rejection [29]. An ideal bone scaffold must have three fundamental features: it should be osteogenic, osteoconductive, and osteoinductive. An osteogenic material can generate bone tissue, which is a characteristic unique to osteoblasts [30]. Thus, the “living” bone can be considered only on the basis of a really osteogenic scaffold. Moreover, to ensure that the osteogenicity is retained in bone grafts, the transplant must be collected and used as quickly as possible to facilitate cell survival after surgical trauma [30, 31]. To fabricate a bone scaffold, an ideal biomaterial must also possess other properties, such as being bio-inert, biocompatible, bioactive, and biodegradable, possessing suitable mechanical properties. Furthermore, the biomaterial should also be able to withstand sterilization in order to avoid infections, and be interconnected and demonstrate controlled porosity [31]. In addition, it should be able to undergo efficient resorption in the course of bone regeneration. The scaffold-cell interaction must also ensure easy penetration, distribution, and proliferation of seeded cells [31]. The biomaterial should be 90% porous, with a suitable pore diameter to enable the cells to penetrate the biomaterial, thus ensuring regrowth of new bone tissue and its optimal vascularization. Finally, it is also essential that the scaffold biomaterial must be efficiently resorbed, with the deposition of new bone tissue, so that the new bone may replace it entirely, while maintaining the shape and thickness [32]. Craniofacial scaffolds (having several applications in dentistry) must fill three-dimensionally complex defects and provide adequate resistance to temporary load during regeneration [33].
Depending on their composition, polymer-based scaffolds can be classified as natural scaffolds, synthetic scaffolds, unblended scaffolds, and composite scaffolds [34]. The desired longevity of the polymeric scaffold implicates the use of bio-inert or biodegradable polymers, and their stability involves application of unblended or composite polymers, whereas the desired cellular interactions guide the choice of naturally- or synthetically-derived polymers [35]. The materials most commonly used for tissue regeneration include calcium phosphate ceramics like hydroxyapatite (HA) and beta-tricalcium phosphate (β-TCP), synthetic polymers such as poly glycolic acid(PGA) and poly(lactic-co-glycolic) acid (PLGA), and naturally occurring biodegradable polymers such as collagen, hyaluronic acid, silk fibroin, gelatin, and chitosan [36].
Natural polymers have good biocompatibility, and they can be easily modified and processed into various structures [37]. However, their provenance from animal sources can increase the risk of pathogen transmission and immune rejection. Moreover, their poor mechanical strength does not assure whole protection of the seeded cells, slowing the healing process and in the worst-case leading to implantation failure [35]. An example is represented by collagen, which is used unblended for cartilage regeneration and, in association with other polymers or materials (composite scaffolds), for bone tissue regeneration. Collagen, hyaluronic acid (HA), carboxymethyl cellulose (CMC), and chitosan are some of the most studied natural polymers for bone regeneration [37].
The advantage of synthetic biodegradable polymer is their versatile behavior. Their properties such as mechanical strength and biodegradation rate depend on their molecular weight and composition, which can be tailored according to specific parameters. However, a lack of biological signalling and the resulting deficiency of cell response are frequent critical issues of this type of polymers [10].
Synthetic polymer degradation is mainly driven by hydrolysis, while natural polymers are degraded mostly through enzymatic pathways or combined with hydrolysis. The most-studied and used synthetic polymers are poly-alpha-hydroxy acids and derivatives, polycaprolactone (PCL) [38].

Stem cells in the scaffolds

The ability of a stem cell to differentiate into many different cell types offers great potential in regenerative medicine [39]. Dependent on their original source, these cells are classified as embryonic stem cells (ESCs) and adult stem cells, with the former extracted from embryos developed from in vitro fertilized eggs, and the latter derived from adult tissue andsupported to maintain and repair the same tissue [40].
In general, the stem cells are divided into three main types that can be utilized for tissue repair and regeneration: 1) the embryonic stem cells derived from embryos (ES); 2) the adult stem cells that are derived from adult tissue; and 3) the induced pluripotent stem (iPS) cells that have been produced artificially via genetic manipulation of the somatic cells [41]. Human ESCs (hESCs), human BMMSCs (hBMMSCs), and human umbilical cord-derived mesenchymal stem cells (hUCMSCs) have mostly been studied for craniofacial tissue engineering. hESCs are harvested from human embryos 5-7 days old, and do not normally exist in the human body [42]. They fall under the pluripotent stemcell classification and have an ability to form three main germ layers: endoderm, mesoderm and ectoderm [43]. They possess the highest pluripotency level, and are able to proliferate quite rapidly. hBMMSCs and hUCMSCs are harvested from bone marrow and the umbilical cord, respectively, and have been extensively studied in the tissue-engineering field [43]. Both cell lines are multipotent and can be differentiated into osteoblasts, chondrocytes, myoblasts, adipocytes, fibroblasts and nerve tissues. hBMMSCs are considered to be the current gold standard cell lines [44]. However, they have certain drawbacks such as an invasive procedure to harvest the cells, a limited number of cells, and lower self-renewal and proliferation capacity due to patient aging and diseases such as arthritis. To avoid these drawbacks, hUCMSCs can be a good replacement [45].
Popular stem cell used in dental tissue engineering is the periodontal ligament stem cells (PDLSC) which is extracted from discarded teeth and has the potential to generate the cementum and periodontal ligament-like structure. Studies have shown that these stem cells also have the potential to develop into the osteogenic and adipogenic tissues in vitro, opening up multiple opportunities for tissue engineering from dental-derived stem cells [46].

Scaffolds and drug delivery

Polymer matrix, or scaffold, represents a 3D platform that may serve the dual purpose of cell support and cells/growth factors (GFs)/drugs delivery [10]. Porosity is perhaps the most important structural scaffold requirement, including macropores (>50 nm, <300 nm) plausible for cell penetration and tissue in-growth, and smaller pores such as micropores (<2 nm) and mesopores (>2 nm, <50 nm) which allow nutrient transport and waste of metabolic products, permitting cell growth. Whenever scaffolds are made of biodegradable polymers, scaffold biodegradation also contributes to the release of a loaded drug. Scaffold degradation rate is a very important parameter to be set, in order to achieve suitable control of drug release. Moreover, scaffold biodegradation should be synchronized with the rate of tissue growth [10].
Enhanced functionality of these already complex matrices has been achieved by incorporating drugs or drugs encapsulated into drug delivery systems [47]. The drug-releasing scaffolds permit local delivery of an adequate dose of bioactive molecules for a desired period, minimizing active agent release to non-targeted sites, supporting and promoting tissue regeneration, which normally occurs over a long time span [48]. From this viewpoint, TE can be viewed as a special case of controlled drug delivery combined with scaffolding materials. Drug-releasing scaffolds are new multifunctional platforms able to achieve drug delivery to specific sites with high loading rates and efficiency, and control the tissue regeneration process [48].
Cells can be seeded onto the 3D polymer scaffolds or 3D-porous matrix, in order to achieve an engineered tissue. Moreover, cell delivery can also be achieved through their microencapsulation, as commonly performed with alginate microcapsules [49].
Depending on the incorporation method used and the biomaterial characteristics (as discussed above), drug release rate may be controlled by various processes, such as diffusion, polymer erosion or degradation, and swelling of polymer followed by diffusion [10, 47]. Drugs release profile can be altered by modifying polymer properties or adjusting physical and chemical properties of the scaffold such as porosity, pore size, and shape, polymer crosslinking degree, and degradation rate [48]. Additionally, drugs and cells can be encapsulated into biodegradable particulate systems having the potential to be retained in specific tissues, providing their sustained release [50].
Biomaterials for drug delivery can be designed in various morphologies (e.g., micelles, vesicles, particles, tubes, scaffolds, or gels) and architecture (reservoirs or matrices) [51]. Drugs can be safely encapsulated in non-cytotoxic and biodegradable synthetic polymers such as polylactic acid (PLA), polyglycolic acid (PGA), their copolymer polylactic-co-glycolic acid (PLGA), poly-ε-caprolactone (PCL), polyethylene, polymethylmethacrylate (PMMA), or natural hydrogels such as alginate, gelatin, fibrin, collagen, and chitosan [52,53].
Worth of note, many biomaterials used for drug delivery systems are the same as for scaffold manufacturing, creating a perfect interaction between the areas of drug delivery and tissue regeneration research [52].

Conclusion

This review article aims to discuss recent advances in craniofacial tissue engineering using polymeric scaffolds. Craniofacial tissue is the region that should meet highest demands in tissue engineering, due to associated aesthetic and functional characteristics required. For the successful regeneration of complex tissue structures and restoration of aesthetic characteristics, numerous biomaterials and scaffolds have been used. Before deciding on biomaterials and scaffolds, we need a good understanding of the complex anatomical structures of craniofacial tissue. We discussed various scaffolds and their possible components used in recent studies.
The studies are addressed to finding biomaterials with properties suitable to support tissue regeneration, and to obtain drug delivery systems which are able to modulate drug release. Such scaffold/drug delivery systems combine several advantages such as:
1) local drug delivery with improved bioavailability and reduced
adverse effects with respect to systemic drug administration;
2) sustained drug release;
3) ability of combining two or more drugs in a single scaffold.
In the future an experimental study of the scaffolds as drug and stem cell carriers is planned with evaluation of local antibacterial action and tissue regeneration.
No conflicts of interest are reported.

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Introduction

Structure of the craniofacial bone tissues

Artificial scaffolds for bone tissue regeneration

Stem cells in the scaffolds

Scaffolds and drug delivery

Conclusion

References

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Р. М.Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова, Санкт-Петербург, Россия 2Институт высокомолекулярных соединений Российской Академии наук, 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(601) "¹Кафедра челюстно-лицевой хирургии и НИИ детской онкологии, гематологии и трансплантологии им. Р. М.Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. Павлова, Санкт-Петербург, Россия
²Институт высокомолекулярных соединений Российской Академии наук, Санкт-Петербург, Россия
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Регенеративная медицина является развивающейся областью биотехнологий, сочетающая различные аспекты медицины, в том числе клеточную и молекулярную биологию, материаловедение и биологическую инженерию для регенерации или замены тканей. Регенерация кости – перспективный подход в стоматологии, и она рассматривается как идеальная клиническая стратегия в лечении болезней, повреждений и дефектов максиллофациальной области. Успехи тканевой инженерии привели к разработке инновативных опорных структур, что дополняется прогрессом в клеточной терапии. Регенерация кости in vitro может достигаться сочетанием стволовых клеток, опорных структур и биоактивных факторов. Возможное улучшение процесса восстановления поврежденных тканей может быть достигнуто путем нагрузки скаффолдов лекарственными веществами, а также генетическим материалом, факторами роста или другими белками, способствующими восстановлению ткани. Данный обзор сосредоточен на различных биоматериалах, применяемых в стоматологии, в качестве потенциальных скаффолдов (субстратов) для регенерации кости при лечении костных дефектов или хирургических вмешательствах. В частности, рассматриваются характеристики и типы таких структур, а также обсуждается литература о локальной доставке антибиотиков при комбинированном применении скаффолдов и систем доставки лекарственных препаратов.

Ключевые слова

Краниофациальная хирургия, скаффолд, тканевая инженерия, стволовые клетки, доставка препаратов.

Regenerative medicine is an emerging field of biotechnology that combines various aspects of medicine including cell and molecular biology, material science and bioengineering – to regenerate, repair or replace tissues. Bone regeneration is a promising approach in dentistry and is considered an ideal clinical strategy in treating diseases, injuries, and defects of the maxillofacial area. Advances in tissue engineering have resulted in the development of innovative scaffold designs, complemented by the progressmade in cell-based therapies. In vitro bone regeneration can be achieved by the combination of stem cells, scaffolds, and bioactive factors. A possible improvement in restoring damaged tissues may be achieved by loading the scaffolds with drug substances, as well as genetic material, growth factors or other proteins, promoting the tissue regeneration. This review focuses on different biomaterials currently used in dentistry, as potential scaffolds for bone regeneration when treating bone defects, or in surgical interventions, including characteristics and types of these scaffolds, and a literature review of local antibiotic delivery by combined usage of scaffolds and drug-delivery systems.

Keywords

Craniofacial surgery, scaffold, tissue engineering, stem cells, drug delivery.

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Yaremenko1, Anna V. Lysenko1, Elizaveta A. Ivanova1, Alexander D. Vilesov1,2, Oleg V. Galibin1, Nikolay L. Petrov1, Pavel A. Kirillov1 1Department of Faciomaxillar Surgery, R. M. Gorbacheva Research Institute of Children Oncology, Hematology and Transplantology, Research Center; The First St. Petersburg State I. P. Pavlov Medical University, St. Petersburg, Russia 2Institute of Macromolecular Compounds Russian Academy of Sciences, 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(590) "Аndrey I. Yaremenko¹, Anna V. Lysenko¹, Elizaveta A. Ivanova¹, Alexander D. Vilesov¹,², Oleg V. Galibin¹, Nikolay L. Petrov¹, Pavel A. Kirillov¹
¹Department of Faciomaxillar Surgery, R. M. Gorbacheva Research Institute of Children Oncology, Hematology and Transplantology, Research Center; The First St. Petersburg State I. P. Pavlov Medical University, St. Petersburg, Russia
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Keywords

Craniofacial surgery, scaffold, tissue engineering, stem cells, drug delivery.

Keywords

Craniofacial surgery, scaffold, tissue engineering, stem cells, drug delivery.

Ключевые слова

Краниофациальная хирургия, скаффолд, тканевая инженерия, стволовые клетки, доставка препаратов.

Ключевые слова

Краниофациальная хирургия, скаффолд, тканевая инженерия, стволовые клетки, доставка препаратов.

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²Институт высокомолекулярных соединений Российской Академии наук, Санкт-Петербург, Россия
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Introduction

Busulfan-based conditioning in various combinations is widely used in allogeneic haematopoietic stem cell transplantation. Busulfan was initially given orally in myeloablative doses. Erratic absorption from the gut and thereby variable bioavailability resulted in deviations from the target exposure to the drug, causing sometimes undue organ toxicity. Therefore many centres began to adjust the doses based on pharmacokinetic measurements. With the introduction of an intravenous (i.v.) formulation, options for the administration were increased. Intravenous administration has widely replaced oral administration, but many centres continue to use the oral route. The role of pharmacokinetic measurements, particularly in i.v. administration, remains unclear. The practice of busulfan administration for conditioning at transplant centres is evidently heterogenic, and details in which the policies of centres are likely to differ include
the route of administration, number of daily doses, use of pharmacokinetic measurements, and adjustment of doses based on obesity. The possible impact of such differences on the outcome is unknown.

Doses and administration of busulfan in conditioning

The classical total dose in myeloablative conditioning is 16 mg/kg orally (or the corresponding dose calculated per m²). The equivalent i.v. dose is 12.8 mg/kg. In recent years, lower doses have been widely used in the so called reduced intensity conditioning (RIC). In RIC, the dose has most commonly been 8 mg/kg orally or the equivalent i.v. dose of 6.4 mg/kg. However, especially with i.v. dosing the RIC doses have varied to some extent.
The two administration routes have their advantages and disadvantages. Oral busulfan administration was the routine for a couple of decades. However, it is characterized by variable absorption from the gut and the risk of increased toxicity in case of high absorption. Moreover, the oral administration route is inconvenient. On the other hand, this drug form is inexpensive. Intravenous infusion avoids absorption variability from the gut and first pass liver metabolism, thus allowing a more precise dosing and easy administration. However, this formulation is rather costly.
Oral administration of conventional fully intensive doses is traditionally performed in four daily doses, 1 mg/kg x 4/day, for 4 consecutive days. There are practical reasons for splitting the daily doses. Large numbers of tablets (usually 2 mg/ tablet) have to be taken, and gastrointestinal irritation and vomiting may complicate the administration. In early studies of i.v. administration, four daily doses were given according to the classical schedule. Later studies have shown that the daily i.v. dose can be given in one dose without adverse consequences. Pharmacokinetic parameters have been shown to be similar with once daily and four times daily schedules [1]. The only difference was a higher peak concentration with the once daily schedule. However, the higher peak concentration did not cause any additional toxicity. Therefore, the present evidence suggests that the daily i.v. dose can be given safely in one dose.

What is the role of pharmacokinetic monitoring for dose adjustment?

Because of variable absorption of busulfan in oral administration, many centres adopted pharmacokinetic monitoring for dose adjustment although the necessity was not uniformly accepted. In i.v. administration with more precise dosing, the role of pharmacokinetic monitoring is still more unclear. In addition to the unclear indications, there may be practical problems with the use of pharmacokinetics. In many institutions the methodology is not available, and especially in RIC with a short schedule there may also be problems in getting the laboratory results in time.
The busulfan metabolism in children differs to some extent from that of adults. The use of busulfan conditioning or the role of pharmacokinetic measurements in paediatric patients are not discussed in this presentation.

Current practice

The Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation (EBMT) has carried out a survey among EBMT centres about their practice in the use of busulfan for conditioning in allogeneic transplantation in adults [2]. One hundred and nine centres sent their reports. Of these, 104 used busulfan for conditioning, 102 in conventional myeloablative doses and 87 in reduced doses. Both myeloablative and reduced doses of busulfan were used in a wide variation of diseases, including myeloid and lymphatic leukaemias, myelodysplastic and myeloproliferative disorders, lymphomas, myeloma, haemoglobinopathies and other inherited disorders.
When myeloablative doses were used, the drug was given i.v. in 90 and orally in 11 centres. In RIC with lower busulfan doses, the route of administration was intravenous in 73 and oral in 10 centres.
Myeloablative oral doses were always given on four days, on each day four doses of 1 mg/kg. In i.v. administration, the myeloablative total dose was most commonly approximately 12.8 mg/kg. Myeloablative i.v. doses were always administered in four days. The number of daily doses was one in 44 centres, two in 4 centres and four in 40 centres. In RIC transplantations, the most common policy was to reduce the number of days from that used in myeloablative conditioning, whereas the daily dose and the administration schedule remained the same. The number of daily busulfan doses in RIC transplantations was one in 33 centres and four in 28 centres.
Seven centres determined the busulfan dose based on body surface area, the rest (97 centres) based on weight.
Overall, 16 of the 104 centres used pharmacokinetic measurements for dose adjustment in myeloablative conditioning, 9 of these also in RIC. There was no difference between centres giving oral or i.v. busulfan in the use of pharmacokinetics for dose adjustment, in full dose conditioning 3/11 vs. 14/90 centres, respectively. In RIC transplantations, pharmacokinetic- based dose adjustment was used in 1/10 centres giving oral busulfan and 8/73 using i.v. busulfan.
Busulfan concentration was measured with liquid chromatography and mass spectrometry in 7 centres, in the remaining ones with liquid chromatography. The parameter used for dose adjustment was area under the curve (AUC) with one exception. The measurements for pharmacokinetics were made after the first dose in 11 of 15 centres. One centre used a test dose 1-2 weeks prior to conditioning.
The timing of the samples for pharmacokinetic measurements in relation to the drug administration as well as the busulfan exposure target ranges varied markedly, no two centres had an identical policy. The practice of dose adjustment based on pharmacokinetics was reported to be the same in myeloablative and reduced intensity conditioning, with one exception.
Seventy-four centres adjusted the dose of busulfan in myeloablative conditioning in obese patients, whereas 25 centres did not. In RIC, 53 centres adjusted the dose whereas 31 did not. In obese patients, the busulfan dose was determined according to actual body weight (12 centres), ideal body weight (15 centres), AIBW-25 (ideal body weight + 0.25 x (actual body weight – ideal body weight) (46 centres), AIBW-40 (12 centres), or other (11 centres). The most common policy of using AIBW-25 is in line with the recommendations of the American Society of Blood and Marrow Transplantation Practice Guidelines Committee [3].

Conclusions

There is a marked variation between centres in the details of busulfan administration for conditioning in allogeneic transplantation. The clinical impact of this variation remains uncertain. Efforts toward a more standardized use of busulfan in the conditioning would be indicated.

Conflict of interest

No conflicts of interest are reported.

References

1. Madden T, de Lima M, Thapar N, Nguyen J, Roberson S, Couriel D, Pierre B, Shpall EJ, Jones RB, Champlin RE, Andersson BS. Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule. Biol Blood Marrow Transplant. 2007;13(1):56-64.

2. Ruutu T, van der Werf SM, van Biezen A, Backman J, Nagler A, Montoto S, Mohty M, Niederwieser D, Langebrake C, Peric Z, Duarte R, Basak G. Use of busulfan in conditioning for allogeneic hematopoietic stem cell transplantation in adults: A survey by the Complications and Quality of Life Working Party of the EBMT. 59th Meeting of the American Society of Hematology, Atlanta, USA, December 9-12, 2017, abstract 1955.

3. Bubalo J, Carpenter PA, Majhail N, Perales MA, Marks DI, Shaughnessy P, Pidala J, Leather HL, Wingard J, Savani BN; American Society for Blood and Marrow Transplantation practice guideline committee. Conditioning chemotherapy dose adjustment in obese patients: a review and position statement by the American Society for Blood and Marrow Transplantation practice guideline committee. Biol Blood Marrow Transplant. 2014;20(5):600-616.

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Introduction

Doses and administration of busulfan in conditioning

What is the role of pharmacokinetic monitoring for dose adjustment?

Current practice

Conclusions

Conflict of interest

No conflicts of interest are reported.

References

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Ранее препарат назначали перорально. Однако индивидуальные различия в абсорбции препарата из кишечника иногда приводят к побочным токсическим эффектам. В последнее время внутривенное введение бусульфана применяют вместо перорального назначения, но многие клиники еще используют и пероральную терапию. Кроме того, различные центры применяют разные схемы его назначения, фармакокинетические исследования для индивидуализации доз препарата. Поэтому целью нашего исследования была оценка классического применения бусульфана в различных трансплантационных клиниках. Рабочая группа Европейского общества трансплантации костного мозга (EBMT) провела исследование среди сентров ТГСК относительно их практики использовании бусульфана для кондиционирования у взрослых пациентов, в том числе – дозы и пути введения препарата, роль фармакогенетического мониторинга. В большинстве клиник бусульфан назначают внутривенно, как в миелоаблативном режиме, так и в режимах сниженной интенсивности. Отмечаются значительные различия между центрами в отдельных моментах назначения бусульфана для кондиционирования. Клинические последствия такой вариабельности остаются невыясненными. Требуются усилия, направленные на более стандартизованное применение бусульфана в кондиционирующей терапии. <h2 style="text-align: justify;">Ключевые слова</h2> Бусульфан, трансплантация гемопоэтических стволовых клеток, способ назначения, дозировка, мониторинг. 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Ранее препарат назначали перорально. Однако индивидуальные различия в абсорбции препарата из кишечника иногда приводят к побочным токсическим эффектам. В последнее время внутривенное введение бусульфана применяют вместо перорального назначения, но многие клиники еще используют и пероральную терапию. Кроме того, различные центры применяют разные схемы его назначения, фармакокинетические исследования для индивидуализации доз препарата. Поэтому целью нашего исследования была оценка классического применения бусульфана в различных трансплантационных клиниках. Рабочая группа Европейского общества трансплантации костного мозга (EBMT) провела исследование среди сентров ТГСК относительно их практики использовании бусульфана для кондиционирования у взрослых пациентов, в том числе – дозы и пути введения препарата, роль фармакогенетического мониторинга. В большинстве клиник бусульфан назначают внутривенно, как в миелоаблативном режиме, так и в режимах сниженной интенсивности. Отмечаются значительные различия между центрами в отдельных моментах назначения бусульфана для кондиционирования. Клинические последствия такой вариабельности остаются невыясненными. Требуются усилия, направленные на более стандартизованное применение бусульфана в кондиционирующей терапии. <h2 style="text-align: justify;">Ключевые слова</h2> Бусульфан, трансплантация гемопоэтических стволовых клеток, способ назначения, дозировка, мониторинг. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3029) "

Кондиционирующая терапия, основанная на применении бусульфана, используется в течение десятилетий при аллогенной трансплантации гемопоэтических клеток (алло-ТГСК). Ранее препарат назначали перорально. Однако индивидуальные различия в абсорбции препарата из кишечника иногда приводят к побочным токсическим эффектам. В последнее время внутривенное введение бусульфана применяют вместо перорального назначения, но многие клиники еще используют и пероральную терапию. Кроме того, различные центры применяют разные схемы его назначения, фармакокинетические исследования для индивидуализации доз препарата. Поэтому целью нашего исследования была оценка классического применения бусульфана в различных трансплантационных клиниках. Рабочая группа Европейского общества трансплантации костного мозга (EBMT) провела исследование среди сентров ТГСК относительно их практики использовании бусульфана для кондиционирования у взрослых пациентов, в том числе – дозы и пути введения препарата, роль фармакогенетического мониторинга. В большинстве клиник бусульфан назначают внутривенно, как в миелоаблативном режиме, так и в режимах сниженной интенсивности. Отмечаются значительные различия между центрами в отдельных моментах назначения бусульфана для кондиционирования. Клинические последствия такой вариабельности остаются невыясненными. Требуются усилия, направленные на более стандартизованное применение бусульфана в кондиционирующей терапии.

Ключевые слова

Бусульфан, трансплантация гемопоэтических стволовых клеток, способ назначения, дозировка, мониторинг.

Busulfan-based conditioning has been used for decades in allogeneic haematopoietic stem cell transplantation (allo-HSCT). Initially, the drug was given orally. However, variable absorption rates from the gut resulted sometimes in adverse toxic effects. Later on, intravenous administration has replaced oral administration, but many centres still use the oral route. Moreover, different centres use various administration schedules and pharmacokinetic assays to individualize busulfan dosage. A Working Party of the European Society for Blood and Marrow Transplantation (EBMT) has carried out a survey among EBMT centres about their practice in the use of busulfan for conditioning in HSCT in adults, including dosage and routes of busulfan administration, and role of pharmacokinetic monitoring. At most centres, busulfan is given intravenously, both in myeloablative and reduced-intensity conditioning. There is marked variation between centres in the details of busulfan administration. The clinical impact of this variation remains uncertain. Efforts toward a more standardized use of busulfan in the conditioning would be indicated.

Keywords

Busulfan, hematopoietic stem cell transplantation, administration route, dosage, monitoring.

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Keywords

Busulfan, hematopoietic stem cell transplantation, administration route, dosage, monitoring.

Keywords

Busulfan, hematopoietic stem cell transplantation, administration route, dosage, monitoring.

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Ранее препарат назначали перорально. Однако индивидуальные различия в абсорбции препарата из кишечника иногда приводят к побочным токсическим эффектам. В последнее время внутривенное введение бусульфана применяют вместо перорального назначения, но многие клиники еще используют и пероральную терапию. Кроме того, различные центры применяют разные схемы его назначения, фармакокинетические исследования для индивидуализации доз препарата. Поэтому целью нашего исследования была оценка классического применения бусульфана в различных трансплантационных клиниках. Рабочая группа Европейского общества трансплантации костного мозга (EBMT) провела исследование среди сентров ТГСК относительно их практики использовании бусульфана для кондиционирования у взрослых пациентов, в том числе – дозы и пути введения препарата, роль фармакогенетического мониторинга. В большинстве клиник бусульфан назначают внутривенно, как в миелоаблативном режиме, так и в режимах сниженной интенсивности. Отмечаются значительные различия между центрами в отдельных моментах назначения бусульфана для кондиционирования. Клинические последствия такой вариабельности остаются невыясненными. Требуются усилия, направленные на более стандартизованное применение бусульфана в кондиционирующей терапии. <h2 style="text-align: justify;">Ключевые слова</h2> Бусульфан, трансплантация гемопоэтических стволовых клеток, способ назначения, дозировка, мониторинг. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3029) "

Ключевые слова

Бусульфан, трансплантация гемопоэтических стволовых клеток, способ назначения, дозировка, мониторинг.

Ключевые слова

Бусульфан, трансплантация гемопоэтических стволовых клеток, способ назначения, дозировка, мониторинг.

Introduction

In allogeneic stem cell transplantation there is a variable degree of immune deficiency due to transient hematopoietic insufficiency, graft-versus-host disease (GVHD) and immunosuppressive treatment for prophylaxis and therapy. These conditions favor infections with various microorganisms; they may be transferred from outside or may reside inside of the patient. The latter could be reactivated from a latent state or symbiotic state. They may be enhanced by the destruction of mucosal barriers in gut, skin or respiratory tract. Various provisions have been taken in order to minimize the acute phase complications; reduced intensity conditioning and anti-infectious prophylaxis were most successful. However, GVHD is still the major problem of allogeneic stem cell transplantation; skin, gut and liver are still primary target organs and lung diseases may further complicate the syndrome. In the absence of GVHD immunosuppressive therapy can be discontinued 4-6 months after transplantation; persistent chimerism in the absence of GVHD and sufficient protection against infections indicate transplantation tolerance. On the other hand, tolerance should not be induced against the leukemia, since the immune reaction of the graft against the host’s leukemia is an essential part of the therapeutic success of allogeneic stem cell transplantation.
The release of cytokines by the host’s immune system during the conditioning phase and prior to transplantation, the so-called “cytokine storm” has a strong impact on the development of acute GVHD and other complications of transplantation [1]. The release of tumor necrosis factor alpha has been described as pathophysiological mechanism of microangiopathy seen after transplantation [2, 3]. Acute inflammatory reactions and GVHD could be modified by prophylactic treatment with anti-TNF-a antibody [4]. Irradiation and chemotherapy can cause severe damage of the gut epithelium, the break of the mucosal barrier allows infections by crossing bacteria. Oral administration of non-absorbable antibiotics and antifungals has been the traditional form of prophylaxis, because survival of high doses of total body irradiation is increased in decontaminated animals. The role of the gut flora for GVHD was studied by van Bekkum et al. [5, 6]: mice received sterile fetal gut implants under the skin prior to irradiation and stem cell transplantation. They found little GVHD in the fetal gut, if the mice were well decontaminated of bacteria, but significant GVHD in conventional mice. The poor acceptance of non-absorbable antibiotics by the patients led to the use of absorbable antibiotics such as fluorchinolon and metronidazole. However, the increasing frequency of resistant bacteria question the use of broad spectrum antibiotic prophylaxis. There is controversy about antibiotic prophylaxis at all with regard to the role of gut flora in the immune homeostasis and its form. Particular emphasis is on the prevention of infections with multi-resistant microorganisms.

Prophylaxis of infections

At the beginning of allogeneic stem cell transplantation, the experience with reverse isolation of newborn children with severe combined immune deficiency were the basis of research of various forms of isolation and gut decontamination [7-11]. Children with severe combined immune deficiency were delivered by Cesarian section and kept in a sterile environment [7]. The colonization of the gut was a risk in immune deficient children housed in a sterile environment. Therefore these children were occasionally “re-conventionalized” by maternal stool [12] after recovery of some immune functions.
In other patients, prophylactic measures against infections were oriented for the duration of severe neutropenia and the extent of immune deficiency. Most external infections can be prevented by reverse isolation in single bed rooms, washing and disinfection of the hands, and wearing face masks by personal and visitors. HEPA-filtered air protects against airborne infections, in particular mold infections [13]. However, the patients may bring along microorganisms, some of which can be dangerous because of prior hospitalization and antibiotic treatment. Antibacterial prophylaxis was originally designed for complete suppression of the intestinal flora. This regimen has been studied with controversial results, significant improvement has been shown in children [7, 8] and patients with aplastic anemia [9]. Complete decontamination is rarely possible and partial or selective decontamination has been proposed [14]. This form of decontamination spares anaerobic bacteria in order to induce resistance to the colonization with pathogenic bacteria. However, complete decontamination including metronidazole was found more successful [15]. The oral non-absorbable antibiotics are not very palatable, and most transplant centers have switched to fluorquinolones that are readily absorbed and better accepted by the patients. Recently improved results were described with rifaximin [30]. Rifaximin preserves anaerobic bacteria and depresses colonization with enterococcal species. Some anaerobic bacteria produce short fatty acid and indolsulfoxide that temper proinflammatory changes. Other preventive measures are more preemptive; e.g., the CMV disease can be prevented by preemptive treatment at the time of increasing PCR positivity or antigenemia; non-invasive respirator support is effective in preventing pneumonia.
The predominant infections in the first 2 to 4 weeks after conditioning and transplantation are associated with severe neutropenia, mainly bacterial infections with Gram-negative and Gram-positive bacteria. Severe neutropenia of more than 10 days duration is often complicated by infections with Gram-positive bacteria and fungi. Nosocomial infections with resistant strains create an increasing problem [16]. Moreover, herpes simplex infections can be reactivated by the conditioning treatment including total body irradiation, and prophylactic treatment with acyclovir has been beneficial.
The period of marrow aplasia ends with the recovery of reticulocytes, granulocytes and platelets. The following period is characterized by immune recovery and graft-versus-host reactions. The period after engraftment until 4-6 months after transplantation is characterized by a slowly recovering immune system and various degrees of immune deficiency and dysfunction. The deficiency is severe in patients with GVHD and its treatment with immunosuppressive medication. Viral infections are frequent and may be life-threatening, fungal infections with Aspergillus are a risk for patients with intense immunosuppression. Encapsulated bacteria can create life-threatening situations in patients with poor antibody responses and splenic atrophy. Immune recovery is improved by higher numbers of stem cells transplanted.
EBV-associated lymphoproliferative disease (PTLD) is more frequent in patients given anti-thymocyte globulin [17] and patients with HLA-mismatched donors [18], CMV infections after the treatment with alemtuzumab [19]. Including the anti-CD20 antibody rituximab into the immunosuppressive conditioning may prevent EBV-associated PTLD [20] because of ablation of B-cells. Anti-viral prophylaxis is commonly given for 4 months after transplantation and the patient should be controlled after discontinuation of anti-viral therapy, because of an increased risk of viral infections after the discontinuation. Antibiotic prophylaxis should be given in patients with acute or chronic GVHD on immunosuppressive therapy, or patients with asplenia syndrome. This can be diagnosed by sonography and the finding of Jolly bodies in red blood cells.
Vaccination against pneumococci, Hemophilus influenzae, meningococci should be given at 6 months after transplantation, preferably as protein-conjugated vaccines [21]. Priorto vaccination, immunosuppressive treatment should be discontinued, and GVHD should be absent; the CD4 count should be more than 200/μl and CD19>20/μl. Live attenuated vaccines should not be given earlier than 2 years after transplantation. Special attention for flu' vaccination is required in the influenza season; sexually active persons may require vaccination against human papillomavirus. Presently there is no clear evidence that vaccination has a negative impact on GVHD.
There is a significant reduction in treatment-related mortality; several factors may be responsible. Major progress came from treatment with better antibiotics, anti-virals and anti-fungals, but also from reducing the intensity of conditioning treatments [22]. In general, acute GVHD is less severe and occurs later in patients conditioned less intensively. Less intensive conditioning liberates less cytokines and particularly TNF-α. Treatment with TNF-α antibody during conditioning treatment [4] tempers the cytokine storm. Shorter period of fever was observed, along with less acute GVHD which occurred at later terms. Moreover, a reduced-intensity conditioning is also associated with diminished damage of epithelial barrier and, thus, prevents translocation of bacteria and their pathogen associated molecular patterns to the gut lymphoid tissues being a pre-requisite for immune activation.
Apart from conditioning and its regimen, preventive measures of infections are extremely important for two reasons: absence of infectious risks allows immunosuppressive treatment of GVHD without overwhelming infections which may incite GVHD by several mechanisms including stimulation of innate immune mechanism, up-regulation of class II HLA, cross-reactivity and epitope spreading [29]. Today we know that innate immunity plays a major role in the induction of GVHD [31-33].
There are several findings pointing to the gut as primary organ of T cell activation in acute GVHD; mice without Peyers patches do not develop acute GVHD [25], blockade of the CXCR5 chemokine receptor with maraviroc reduces acute GVHD in patients [26, 27], patients with mutations in intracellular defense to bacteria (NOD/CARD2) develop more GVHD [28]. Therefore, the gut plays a decisive role in the initiation of GVHD and the patients' fate with GVHD. Interestingly, gut GVHD does not correlate with graft-versus-leukemia activity.
The impact of the intensity of conditioning varies between diseases and stages of the disease. In many instances control of leukemia was not achieved by the intensity of conditioning, but an immune reaction of donor lymphocytes against the leukemia [23, 24].

The gut microbiome and GVHD

Early experiments of R. Truitt and colleagues had shown that mice could be cured of AKR leukemia and SJL lymphoma by allogeneic transplantation; they survived, if their gut was germ-free [34, 35]. Several studies have shown superior survival with successful gut decontamination [8] [10], but others failed to improve survival after allogeneic stem cell transplantation for leukemia [11]. Prevention of infection with potentially pathogenetic bacteria translocated from the intestinal flora is one aspect, initiation of immune responses and building up of an immune repertoire is the other aspect. The gastrointestinal mucosa is an important part of the immune system, and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. Blood group isoagglutinins are produced after colonization with E. Coli and even transient colonization of the mother’s gut during pregnancy improves the immune reactivity in the cubs [36]. There are genetic and dietary conditions that determine the composition of the gut flora [37]. In the meantime many gut associated immune mechanisms have been clarified, not only microbiota, but also food antigens drive the development of the immune system to immunity and tolerance [38]. Tolerance against solid food is mediated by regulatory T cells induced by CD103 + and CD11c+ dendritic cells in the gut mucosa; regulatory T cells induced by microbial antigens persist longer than those evoked by food antigens. The role of adaptive immune responses and the antigens involved is not well defined. Any way, the gut microbiome may represent an important part of the immune repertoire of each individual [39].
Most investigations of intestinal microbiology were directed to mechanisms of innate immunity that may or may not be important to alloimmune responses. Intracellular microbial pattern recognition receptors (NOD/CARD2) [40] have a role in GVHD and other complications of allogeneic transplantation; mutations in the donor’s and the host’s cells increase the risk of complications. Interestingly, this is not the case in patients decontaminated with the traditional non-absorbable antibiotics (unpublished). Paneth cells produce antimicrobial peptides like Reg IIIa; increased serum levels are early indicators of gut GVHD [41]. Similarly, fecal calprotectin is produced by activated macrophages, it has been described as biomarker for gut GVHD and refractoriness to steroid therapy [42]. The destruction of the mucosal barrier during conditioning and GVH-reactions against the gut epithelium enhances translocation of bacteria from the gut lumen to the blood flow [31, 43], diarrhea followed by septicemia and pneumonia has a dismal prognosis.
Surveillance cultures of the microbial flora of the intestine were performed since the start of stem cell transplantation in the 70s [7], but the success was variable and GVHD resulting in colonization with single strains resistant to the treatment was observed. Recently, diagnostic tools have improved by testing of bacterial 16S RNA genes. A great variety of bacteria can be detected, the greater the diversity the lesser GVHD [44]. However, not only the host’s immune system determines the composition of microbiota, but the flora itself is controlling its composition creating colonization resistance. B.thetaiotamicron, B.thuringiensis, Bifidobacteria spp play a role in controlling the colonization of the gut [45].
The composition of intestinal microbiota seems to play an important role for the pathophysiology of intestinal GvHD. Commensal bacteria, particularly Clostridiales, like Blautia, have been shown to be associated with less GvHD [46]. These results were confirmed as low levels of 3-indoxylsuflate, a tryptophan metabolite of Clostridiales, early after transplantation have been observed to correlate with poor outcome and increased GvHD-related TRM [47]. Modulation of intestinal microbiota composition may influence the occurrence and severity of gut GvHD as shown in experimental murine models fed with Lactobacillae [48] or butyrate- producing Clostridiales.
The mechanism by which anaerobic bacteria suppress GVHD is still unknown, most likely it is the secretion of protective metabolites like short chain fatty acids or indole and its derivatives. They exert a lot of anti-inflammatory effects and contribute to the maintenance of epithelial integrity and immunological homeostasis. Recently a role for indoxylsulfate was defined in patients with GVHD. Indoxyl sulfate is produced by anaerobic bacteria and protects the mucosal barrier.
The form of gut decontamination has also an important impact on GVHD; rifaximin is a broad-spectrum antibiotic with negligible gastrointestinal resorption that spares anaerobic bacteria and improves indoxyl sulfate production [30]. As compared to ciprofloxacin and metronidazole for gut decontamination rifaximin preserves high microbiome diversity and was associated with less severe GI GvHD and improved survival. The beneficial effect of rifaximin was independent of poor prognostic factors as the mutated genotype of NOD CARD2 and treatment with systemic antibiotics prior to transplantation [48].
Even the kind and timepoint of use of systemic broad-spectrum antibiotics for therapy of neutropenic infections seem to impact GI GvHD. The avoidance of imipenem/cilastatin and piperacillin/tazobactam during the neutropenic period improved survival by decreasing GVHD [49]. These antibiotics favored the growth of Akkermannsia muciniphilia, a bacterium with mucus degrading capabilities, that may contribute to the development of intestinal inflammation and GvHD. Aztreonam and cefipime, both antibiotics with anaerobic sparing effects may be preferable under this condition. However, also the time of starting therapeutic antibioticscan influence gastrointestinal GvHD as antibiotic use before the day of transplantation contributed to severe intestinal dysbiosis and poor outcome of patients after ASCT.
However, a more general effect of immunoregulation by microbiota can be expected. A large variety of immunoregulatory cells in the gut depends on the presence of short chain fatty acids (regulatory T cells), on arylhydorcarbon acid ligands such as indoles (ILCs type 3) or on bacterial products like vitamins (invaraint NKT cells). Microbiote dysruption thus interferes with a well tuned balance of immunregulatoy cells which is essential for tissue tolerance.
A most encouraging observation was the finding that colonization with certain groups of bacteria (Eubacteriaceae) like Enterobacterium limosum is associated with a decreased relapse rate [50]. The antileukemic mechanism is not well understood. Possibly inhibition of inflammatory changes in the gut improve the control of the disease. Stimulation of CD8 T cells via toll-like receptor binding may be another cause [51] as well as the inhibition of checkpoint inhibitors CTLA- 4 [52] and PD-1L [53] that are influenced by the microbiomeof the gut.
Therefore, the gut microbiome has an as yet poorly defined impact on the structure of the immune system; it certainly contributes to the development of an immune repertoire, the prevention of autoimmune disease and the situation of allogeneic stem cell transplantation, foreign immune cells not only encounter histocompatibility differences, but also a new microbial environment and innate defense mechanisms of the gut.

Viral Infection

Viral infections are a particular challenge for allogeneic T cells, because they are strictly intracellular; the activation of cellular immune responses require signals of activation on the cell surface. Except for viremia antibodies are not required, viruses can spread from cell to cell. Most problems are from reactivation of persistent or latent viral infections, although primary infections do occur. Immune deficiency is the primary cause for viral reactivation, the immune reaction against cells with latent viral infection may contribute to viral reactivation. This way a vicious circle may ensue with GVHD and CMV exchanging each other.
Prototypes for reactivation are infections with herpesviruses: herpes simplex virus (HSV), herpes zoster virus (HZV), cytomegalovirus (CMV) and Epstein Barr virus (EBV), but also other viruses may produce disease after activation, like BK and JC virus, adeno-virus, hepatitis viruses, papilloma virus and others. Clinical herpes simplex infections have been greatly reduced by the prophylactic treatment with acyclovir. Unfortunately, acyclovir is not very effective in CMV infections and CMV associated interstitial pneumonitis and colitis have been great clinical problems in allogeneic stem cell transplantation. The introduction of more effective antiviral drugs and better diagnostic has changed the dangers of CMV infections, prophylactic or preemptive treatment with ganciclovir in case of increasing quantitative PCR loads in blood could prevent disease. CMV is often found in biopsies of patients with GVHD [54-56] and inflammatory bowel disease [57]. CMV infection is a serious complication of gut GVHD and contributes to mortality. However, it may also contribute to GVHD as it has been described for CD4 T cells that induce GVHD via inflammatory signals increasing the expression of HLA class II on non-hematopoietic cells [58]. On the other hand, CD4 T cells are necessary in order to control CMV disease [59] [60, 61]. More recently cross-reactive peptides have been described between CMV and minor histocompatibility antigens [54]. In patients with AML, a successful control of CMV infection during the first 100 days after transplantation correlated with a decreased risk of relapse [62].
Reactivation of HHV-6 is seen in nearly 50% of patients with allogeneic transplants, but it is still not clear whether HHV-6 has a pathogenic role in GVHD. We observed HHV-6 in skin biopsies taken for GVHD that did not respond to steroids [unpublished]. HHV6 genes are integrated in the human genome in 1-3% of patients and donors; in these patients GVHD may be more frequent [63]. In retrospective reviews HHV-6 was associated with bone marrow failure, skin rash, enteritis and CNS disease [64], but the associations were not strong.
Therefore, the interaction of viral infection and GVHD may be mutual: immune deficiency related to GVHD and its treatment favors reactivation of viral infections, and they may provide the inflammatory environment to stimulate GVHD. The inflammatory environment is a potent condition for reactivation of latent virus [65].
Immunotherapy of viral infection with specific cytotoxic T cells has been successful in patients with post-transplant lymphoproliferative disease (PTLD) with reactivation of EBV. An important risk factor of PTLD is the treatment with antithymocyte globulin and anti-T-cell antibodies. Again, it is not known why some anti-T-cell antibodies have a high risk of PTLD and others a rather low risk. Severe adenovirus infections can be associated with GVHD of the gastrointestinal tract, reactivation and new infections may occur, risk factors are GVHD and immune suppression [66]. In some cases with severe diarrhea rota virus is found together with adenovirus.
Hepatitis virus infection presents an important differential diagnosis of GVHD of the liver. Hepatitis B virus may be reactivated in patients with a history of hepatitis as evident by anti-core antibodies, even in the presence of anti-surface antibodies. An antiviral prophylaxis is indicated in patients with long-term immune suppression, antiviral therapy is indicated during transplantation and until a year after discontinuation of immune suppression [67]. The presence of hepatitis C is not considered as a contraindication against allogeneic transplantation, but it should be treated in order to prevent cirrhosis and hepatic carcinoma [68]. In a matched control study, the outcome for patients with hepatitis C virus infection was worse than in the control group [69]. As a rule, patients are not tested for hepatitis E, but recently infections with hepatitis E have been described [70]. Again, elevated transaminases may be considered as an evidence for liver GVHD, but hepatitis E disease may also be present. This infection is rarely associated with clinical disease, but in immunosuppressed patients it may cause mild hepatitis. Treatment with ribavirin and interferon-a can be used for the control of the disease (unpublished observation).
The role of viral infections in GVHD may be variable, reactivation of hepatitis virus is enhanced by immune suppression and the clinical manifestation of hepatitis occurs with the recovering immunity. Therefore, the use of cytotoxic T cells against hepatitis virus may be harmful. In contrast the use of specific cytotoxic T cells against EBV may be life-saving in cases of EBV reactivation and post-transplant lymphoproliferative disease (PTLD) [71, 72].
Adenovirus infections are more frequent in pediatric patients; prolonged viremia can be seen, reactivation may occur from tonsils, nasopharyngeal and gastrointestinal mucosa. This can be observed prior to the development of GVHD, possibly by inducing an inflammatory response. The use of specific Th1 helper cells against adenovirus was successful in controlling adenovirus disease in 15 of 30 patients; increased GVHD was not observed, but 15 patients died with and without a response to T cells [66, 73]. Adeno-virus specific T cells were collected by the interferon-capture technique and resulted in a 70% specific T cells. Non-selected donor lymphocytes were also effective, but carried the risk of GVHD [74] [own unpublished observation]. Adenovirus induces an inflammatory response that may precipitate GVHD [75].
These observations strongly support the treatment of opportunistic and reactivated viral infections while treating GVHD with immune suppression.
A recent study on the gut virome on 44 patients has described a viral “bloom” of DNA viruses following stem cell transplantation that increased in patients with GVHD with a decrease in phage richness [76]. However, only picobirnaviruses were predictive of severe enteric GVHD. These were detected in 40,9% of patients and correlated with fecal levels of calprotectin and a-1 antitrypsin.

Transkingdom control

The microbiome has already achieved much attention by transplanters and the medical community; the virome is gaining increasing attention [76]. However, the microbial environment consists also of interactions of various elements. Viral infections may provide the soil for fungal and bacterial infections, but interactions of virus, bacteria, fungi, nematodes and host mucosa may complicate the picture. Norovirus, retrovirus, rotavirus, astrovirus, picornavirus, adenovirus and herpesvirus have intimate regulatory relationship with bacterial microbiota, their phages, helminthes and fungi [77]. Norovirus have ligands to human blood group antigens including secretory antigens and mucus, but also for certain bacteria [78]. In cases of transkingdom activity, norovirus may induce severe intestinal GVHD presumably involving carbohydrate antigens and antibodies (personal observation).
A still largely unknown but highly important mechanism of transkingdom interactions may be the control of microbiome by viral phages. The most recent studies on succesful treatments with fecal microbiota transfer suggest that co-transplanted phages may exert strongest effects upon the microbiome [79].
Part of the transkingdom mechanism is certainly the host’s reaction against microorganisms that is genetically predisposed and activated by otherwise harmless microorganisms. More information is available on individual genetic background and activation of Th1,2,17 cells that may determine autoimmune activity in the gut [80]. This genetically determined activation of T cells may be equally important in allogeneic transplantation.

Conclusions

Major progress has been achieved by the selection of the best donors with histocompatibility testing, prevention of viral, bacterial and fungal infections with improved antibiotics, antiviral and antifungal treatment as well as less intense conditioning regimens [81]. GVHD is still the major problem of allogeneic stem cell transplantation. There are several encouraging new ways to prevent and to treat GVHD including modification of the gut microbiome [30, 49, 82]; it is now time to select donors according to their immune repertoire and their genetic background for T cell activation. Possibly this can be combined with an anti-leukemic effect based on anti-microbial activity [50, 62] and HLA class II DP histocompatibility [83]. The immune repertoire may be primed by prior infections as they may be primed by prior transfusions and pregnancies, but activation may be decisive that is induced by the actual microbiome and determined genetically by the donor and the host.

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" ["~DETAIL_TEXT"]=> string(47090) "

Introduction

Prophylaxis of infections

The gut microbiome and GVHD

Viral Infection

Transkingdom control

Conclusions

References

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Иммунодефицит различной степени возникает как следствие иммунной супрессии до тех пор, пока не сформируется донорская иммунная система; РТПХ и иммуносупрессивная терапия для профилактики и лечения РТПХ могут вызвать задержку ее восстановления. Эта ситуация способствует инфицированию различными микроорганизмами. Некоторые усовершенствования в профилактике и лечении инфекций, а также снижение интенсивности режимов кондиционирования и улучшение профилактики РТПХ привели к снижению токсичности лечения и смертности, связанной с трансплантацией. Совершенствование терапии антибиотиками бактериальных, а также вирусных и грибковых инфекций внесло свой вклад в развитие этого успеха. Однако инфекции с РТПХ и без нее остаются основным препятствием для алло-ТГСК и иммунотерапии. Новые диагностические средства для исследования цитокинов, выделяющихся в период кондиционирования, состав микробиоты кишечника и ее изменения после ТГСК, а также врожденный иммунитет слизистой кишечника привнесли новый взгляд на патофизиологию РТПХ. Желудочно-кишечный тракт (ЖКТ) является первичным органом активации Т-лимфоцитов при острой РТПХ, и встречаемость РТПХ ассоциирована с меньшим разнообразием микроорганизмов в ЖКТ. Наличие определенных видов анаэробных бактерий ассоциируется со сниженным риском РТПХ и рецидивов лейкоза. Недавние исследования показали, что колонизации ЖКТ некоторыми штаммами Blautia ассоциированы с меньшим риском РТПХ, а ряд линий Limus (Eubacteriaceae) связан со снижением частоты рецидивов. Этот антилейкозный механизм не вполне выяснен. Частой находкой здесь является продукция короткоцепочечных жирных кислот. Таким образом, вопрос о полной или избирательной деконтаминации ЖКТ пока не разрешен. Улучшение выживаемости было описано при деконтаминации рифамиксином, что связывают с выживанием анаэробов и повышенной продукцией индоксилсульфата. Предпринимались попытки лечения РТПХ кишечника путем переноса стула здоровых лиц, что приносило некоторый успех. Это может не только оказывать положительный эффект на бактериальную флору, но и на их взаимодействие с фагами и другими микроорганизмами. Нынешние исследования вирома показали присутствие пикорнавируса, ассоциированного с РТПХ. Слизистая ЖКТ является важной частью иммунной системы, и имеется тонкое равновесие между флорой как таковой и иммунологическим надзором со стороны иммунной системы организма-хозяина. Имеется достаточно доказательств того, что иммунная система слизистых оболочек играет важнейшую роль в развитии иммунного ответа у больных против пищевых антигенов и микробных антигенов, тем самым различая иммунные реакции и иммунную толерантность. Вирусные инфекции, как известно, прокладывают путь для последующих грибковых и бактериальных инфекций, но сложные взаимодействия между вирусами, бактериями грибками, нематодами и слизистой оболочкой могут осложнять общую картину. До сих пор во многом не ясно, насколько важен взаимный контроль различных царств микробиоты и он может быть связан с малоизученной ролью бактериофагов которые могут модулировать микробную колонизацию. Эти взаимодействия могут осложняться применением в клинике абсорбируемых и неабсорбируемых антибиотиков, антивирусных и других препаратов. Есть и некоторые перспективные способы предотвращения и лечения РТПХ. Так, можно выбирать доноров в соответствии с их иммунным репертуаром и генетическим фоном для активации Т-клеток. Возможно, этот подход может сочетаться с антилейкемическим эффектом, основанным на антимикробной активности и тканевой совместимости по HLA (класс II DP-гены). В общем, иммунная активация может быть важной в аспекте ее индукции имеющейся микробиотой, и она определяется генетическими факторами донора и реципиента. <h2 style="text-align: justify;">Ключевые слова</h2> Аллогенная трансплантация гемопоэтических клеток, реакция «трансплантат против хозяина», инфекции, профилактика, микробиота желудочно-кишечного тракта, генетические факторы, антиинфекционная терапия. 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["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) "20086" ["VALUE"]=> array(2) { ["TEXT"]=> string(533) "1Кольб Консалтинг Мюнхен, Германия 2Департамент гематологии и онкологии, клиника внутренних болезней III университетского медицинского центра, Регенсбург, Германия 3Школа медицины Рибейрао-Прето, Университет Сан-Пауло, Бразилия " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(473) "¹Кольб Консалтинг Мюнхен, Германия
²Департамент гематологии и онкологии, клиника внутренних болезней III университетского медицинского центра,
Регенсбург, Германия
³Школа медицины Рибейрао-Прето, Университет Сан-Пауло, Бразилия
" ["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) "20087" ["VALUE"]=> array(2) { ["TEXT"]=> string(7851) " Роль инфекций при аллогенной трансплантации стволовых клеток (алло-ТГСК) и реакции «трансплантат против хозяина» (РТПХ) заново приобрела интерес ввиду нескольких разработок последних лет. Иммунодефицит различной степени возникает как следствие иммунной супрессии до тех пор, пока не сформируется донорская иммунная система; РТПХ и иммуносупрессивная терапия для профилактики и лечения РТПХ могут вызвать задержку ее восстановления. Эта ситуация способствует инфицированию различными микроорганизмами. Некоторые усовершенствования в профилактике и лечении инфекций, а также снижение интенсивности режимов кондиционирования и улучшение профилактики РТПХ привели к снижению токсичности лечения и смертности, связанной с трансплантацией. Совершенствование терапии антибиотиками бактериальных, а также вирусных и грибковых инфекций внесло свой вклад в развитие этого успеха. Однако инфекции с РТПХ и без нее остаются основным препятствием для алло-ТГСК и иммунотерапии. Новые диагностические средства для исследования цитокинов, выделяющихся в период кондиционирования, состав микробиоты кишечника и ее изменения после ТГСК, а также врожденный иммунитет слизистой кишечника привнесли новый взгляд на патофизиологию РТПХ. Желудочно-кишечный тракт (ЖКТ) является первичным органом активации Т-лимфоцитов при острой РТПХ, и встречаемость РТПХ ассоциирована с меньшим разнообразием микроорганизмов в ЖКТ. Наличие определенных видов анаэробных бактерий ассоциируется со сниженным риском РТПХ и рецидивов лейкоза. Недавние исследования показали, что колонизации ЖКТ некоторыми штаммами Blautia ассоциированы с меньшим риском РТПХ, а ряд линий Limus (Eubacteriaceae) связан со снижением частоты рецидивов. Этот антилейкозный механизм не вполне выяснен. Частой находкой здесь является продукция короткоцепочечных жирных кислот. Таким образом, вопрос о полной или избирательной деконтаминации ЖКТ пока не разрешен. Улучшение выживаемости было описано при деконтаминации рифамиксином, что связывают с выживанием анаэробов и повышенной продукцией индоксилсульфата. Предпринимались попытки лечения РТПХ кишечника путем переноса стула здоровых лиц, что приносило некоторый успех. Это может не только оказывать положительный эффект на бактериальную флору, но и на их взаимодействие с фагами и другими микроорганизмами. Нынешние исследования вирома показали присутствие пикорнавируса, ассоциированного с РТПХ. Слизистая ЖКТ является важной частью иммунной системы, и имеется тонкое равновесие между флорой как таковой и иммунологическим надзором со стороны иммунной системы организма-хозяина. Имеется достаточно доказательств того, что иммунная система слизистых оболочек играет важнейшую роль в развитии иммунного ответа у больных против пищевых антигенов и микробных антигенов, тем самым различая иммунные реакции и иммунную толерантность. Вирусные инфекции, как известно, прокладывают путь для последующих грибковых и бактериальных инфекций, но сложные взаимодействия между вирусами, бактериями грибками, нематодами и слизистой оболочкой могут осложнять общую картину. До сих пор во многом не ясно, насколько важен взаимный контроль различных царств микробиоты и он может быть связан с малоизученной ролью бактериофагов которые могут модулировать микробную колонизацию. Эти взаимодействия могут осложняться применением в клинике абсорбируемых и неабсорбируемых антибиотиков, антивирусных и других препаратов. Есть и некоторые перспективные способы предотвращения и лечения РТПХ. Так, можно выбирать доноров в соответствии с их иммунным репертуаром и генетическим фоном для активации Т-клеток. Возможно, этот подход может сочетаться с антилейкемическим эффектом, основанным на антимикробной активности и тканевой совместимости по HLA (класс II DP-гены). В общем, иммунная активация может быть важной в аспекте ее индукции имеющейся микробиотой, и она определяется генетическими факторами донора и реципиента. <h2 style="text-align: justify;">Ключевые слова</h2> Аллогенная трансплантация гемопоэтических клеток, реакция «трансплантат против хозяина», инфекции, профилактика, микробиота желудочно-кишечного тракта, генетические факторы, антиинфекционная терапия. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(7755) "

Роль инфекций при аллогенной трансплантации стволовых клеток (алло-ТГСК) и реакции «трансплантат против хозяина» (РТПХ) заново приобрела интерес ввиду нескольких разработок последних лет. Иммунодефицит различной степени возникает как следствие иммунной супрессии до тех пор, пока не сформируется донорская иммунная система; РТПХ и иммуносупрессивная терапия для профилактики и лечения РТПХ могут вызвать задержку ее восстановления. Эта ситуация способствует инфицированию различными микроорганизмами. Некоторые усовершенствования в профилактике и лечении инфекций, а также снижение интенсивности режимов кондиционирования и улучшение профилактики РТПХ привели к снижению токсичности лечения и смертности, связанной с трансплантацией.
Совершенствование терапии антибиотиками бактериальных, а также вирусных и грибковых инфекций внесло свой вклад в развитие этого успеха. Однако инфекции с РТПХ и без нее остаются основным препятствием для алло-ТГСК и иммунотерапии. Новые диагностические средства для исследования цитокинов, выделяющихся в период кондиционирования, состав микробиоты кишечника и ее изменения после ТГСК, а также врожденный иммунитет слизистой кишечника привнесли новый взгляд на патофизиологию РТПХ. Желудочно-кишечный тракт (ЖКТ) является первичным органом активации Т-лимфоцитов при острой РТПХ, и встречаемость РТПХ ассоциирована с меньшим разнообразием микроорганизмов в ЖКТ. Наличие определенных видов анаэробных бактерий ассоциируется со сниженным риском РТПХ и рецидивов лейкоза. Недавние исследования показали, что колонизации ЖКТ некоторыми штаммами Blautia ассоциированы с меньшим риском РТПХ, а ряд линий Limus (Eubacteriaceae) связан со снижением частоты рецидивов. Этот антилейкозный механизм не вполне выяснен. Частой находкой здесь является продукция короткоцепочечных жирных кислот. Таким образом, вопрос о полной или избирательной деконтаминации ЖКТ пока не разрешен. Улучшение выживаемости было описано при деконтаминации рифамиксином, что связывают с выживанием анаэробов и повышенной продукцией индоксилсульфата. Предпринимались попытки лечения РТПХ кишечника путем переноса стула здоровых лиц, что приносило некоторый успех. Это может не только оказывать положительный эффект на бактериальную флору, но и на их взаимодействие с фагами и другими микроорганизмами.
Нынешние исследования вирома показали присутствие пикорнавируса, ассоциированного с РТПХ.
Слизистая ЖКТ является важной частью иммунной системы, и имеется тонкое равновесие между флорой как таковой и иммунологическим надзором со стороны иммунной системы организма-хозяина. Имеется достаточно доказательств того, что иммунная система слизистых оболочек играет важнейшую роль в развитии иммунного ответа у больных против пищевых антигенов и микробных антигенов, тем самым различая иммунные реакции и иммунную толерантность.
Вирусные инфекции, как известно, прокладывают путь для последующих грибковых и бактериальных инфекций, но сложные взаимодействия между вирусами, бактериями грибками, нематодами и слизистой оболочкой могут осложнять общую картину. До сих пор во многом не ясно, насколько важен взаимный контроль различных царств микробиоты и он может быть связан с малоизученной ролью бактериофагов которые могут модулировать микробную колонизацию. Эти взаимодействия могут осложняться применением в клинике абсорбируемых и неабсорбируемых антибиотиков, антивирусных и других препаратов.
Есть и некоторые перспективные способы предотвращения и лечения РТПХ. Так, можно выбирать доноров в соответствии с их иммунным репертуаром и генетическим фоном для активации Т-клеток. Возможно, этот подход может сочетаться с антилейкемическим эффектом, основанным на антимикробной активности и тканевой совместимости по HLA (класс II DP-гены). В общем, иммунная активация может быть важной в аспекте ее индукции имеющейся микробиотой, и она определяется генетическими факторами донора и реципиента.

Ключевые слова

Аллогенная трансплантация гемопоэтических клеток, реакция «трансплантат против хозяина», инфекции, профилактика, микробиота желудочно-кишечного тракта, генетические факторы, антиинфекционная терапия.

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" ["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) "20089" ["VALUE"]=> array(2) { ["TEXT"]=> string(307) " 1Kolb Consulting UG, München, Germany 2Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany 3Ribeirao Preto School of Medicine, Sao Paulo University, Brazil" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(259) " ¹Kolb Consulting UG, München, Germany
²Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany
³Ribeirao Preto School of Medicine, Sao Paulo University, Brazil" ["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) "20090" ["VALUE"]=> array(2) { ["TEXT"]=> string(5658) "The role of infections in allogeneic stem cell transplantation and graft-versus-host disease has gained a renewed interest because of several developments in recent years. Variable degrees of immune deficiency exist as a consequence of immune suppression until the immune system of donor origin is established; graft-versus-host disease (GVHD) and immunosuppressive treatment for prophylaxis and therapy may delay the restoration. These conditions favor infections with various microorganisms. Several improvements in prophylaxis and treatment of infections as well as reduced intensity of the conditioning regimens and improved prophylaxis of GVHD have decreased toxicity of the treatment and transplant-related deaths. Improved antibiotics, antiviral and antifungal treatment have contributed to the greater success. However, infections with and without GVHD remain a major obstacle of allogeneic stem cell transplantation and immunotherapy. New diagnostic tools for the study of cytokines released during conditioning, the composition and alteration of the gut microbiome after transplantation and the innate immunity of the gut mucosa have given new insights into the pathophysiology of GVHD. The gut is a primary organ of T cell activation in acute GVHD; the incidence of GVHD is associated with a lower gut microbial diversity. The composition of intestinal microbiota seems to play an important role for the pathophysiology of intestinal GvHD. Commensal bacteria, particularly Clostridiales, like Blautia, have been shown to be associated with less GvHD. The mechanism by which anaerobic bacteria suppress GVHD is still unknown, most likely due to secretion of protective metabolites like short chain fatty acids or indole and its derivatives, thus exerting antiiflammatory effects and contribute to epithelial integrity and immunological homeostasis. Modulation of intestinal microbiota composition may influence the occurrence and severity of gut GvHD. The form of gut decontamination has also an important impact on GVHD. E.g., rifaximin is a broad-spectrum antibiotic with negligible gastrointestinal resorption that spares anaerobic bacteria and improves indoxyl sulfate production. Rifaximin preserves high microbiome diversity upon gut decontamination, as compared to ciprofloxacin and metronidazole being associated with less severe GI GvHD and improved survival. Even kind and timely use of systemic broad-spectrum antibiotics for therapy of neutropenic infections seems to impact gut GvHD. E.g., avoidance of imipenem/cilastatin and piperacillin/tazobactam seems to improve survival by decreasing GVHD rates, probably, due to growth of Akkermannsia muciniphilia with mucus-degrading capabilities, thus, probably, promoting intestinal inflammation and GvHD. Aztreonam and cefipime, both antibiotics with anaerobic sparing effects, may be preferable. Use of antibiotics before the day of transplantation may contribute to severe intestinal dysbiosis and poor outcome of patients after ASCT. The presence of certain strains of anaerobic bacteriae is associated with lower risks of GVHD and relapse of leukemia. Recent studies have shown that gut colonization with some strains of Blautia is associated with lesser risk of GVHD, and strains of Limus (Eubacteriaceae) is associated with a decreased relapse rate. This antileukemic mechanism is not well understood. A common finding is the production of short chain fatty acids. Hence, the question of total or selective gut decontamination is discussed controversially. Improved survival was described with the decontamination with rifaximin that is associated with surviving anaerobes and an increased production of indolsulfoxide. Treatment of GVHD of the gut has been attempted with the transfer of stool from a healthy person with some success. This may not only be the beneficial impact of bacteriae, but the composition of bacteriae with phages and other microorganisms. A recent study of the viriome found the presence of picobrna virus associated with GVHD. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs. There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host. <h3>Keywords</h3> Allogeneic hematopoietic cell transplantation, graft-versus-host disease, infection, prevention, gut micro" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5598) "The role of infections in allogeneic stem cell transplantation and graft-versus-host disease has gained a renewed interest because of several developments in recent years. Variable degrees of immune deficiency exist as a consequence of immune suppression until the immune system of donor origin is established; graft-versus-host disease (GVHD) and immunosuppressive treatment for prophylaxis and therapy may delay the restoration. These conditions favor infections with various microorganisms. Several improvements in prophylaxis and treatment of infections as well as reduced intensity of the conditioning regimens and improved prophylaxis of GVHD have decreased toxicity of the treatment and transplant-related deaths.
Improved antibiotics, antiviral and antifungal treatment have contributed to the greater success. However, infections with and without GVHD remain a major obstacle of allogeneic stem cell transplantation and immunotherapy. New diagnostic tools for the study of cytokines released during conditioning, the composition and alteration of the gut microbiome after transplantation and the innate immunity of the gut mucosa have given new insights into the pathophysiology of GVHD. The gut is a primary organ of T cell activation in acute GVHD; the incidence of GVHD is associated with a lower gut microbial diversity.
The composition of intestinal microbiota seems to play an important role for the pathophysiology of intestinal GvHD. Commensal bacteria, particularly Clostridiales, like Blautia, have been shown to be associated with less GvHD. The mechanism by which anaerobic bacteria suppress GVHD is still unknown, most likely due to secretion of protective metabolites like short chain fatty acids or indole and its derivatives, thus exerting antiiflammatory effects and contribute to epithelial integrity and immunological homeostasis. Modulation of intestinal microbiota composition may influence the occurrence and severity of gut GvHD.
The form of gut decontamination has also an important impact on GVHD. E.g., rifaximin is a broad-spectrum antibiotic with negligible gastrointestinal resorption that spares anaerobic bacteria and improves indoxyl sulfate production. Rifaximin preserves high microbiome diversity upon gut decontamination, as compared to ciprofloxacin and metronidazole being associated with less severe GI GvHD and improved survival.
Even kind and timely use of systemic broad-spectrum antibiotics for therapy of neutropenic infections seems to impact gut GvHD. E.g., avoidance of imipenem/cilastatin and piperacillin/tazobactam seems to improve survival by decreasing GVHD rates, probably, due to growth of Akkermannsia muciniphilia with mucus-degrading capabilities, thus, probably, promoting intestinal inflammation and GvHD. Aztreonam and cefipime, both antibiotics with anaerobic sparing effects, may be preferable. Use of antibiotics before the day of transplantation may contribute to severe intestinal dysbiosis and poor outcome of patients after ASCT.
The presence of certain strains of anaerobic bacteriae is associated with lower risks of GVHD and relapse of leukemia. Recent studies have shown that gut colonization with some strains of Blautia is associated with lesser risk of GVHD, and strains of Limus (Eubacteriaceae) is associated with a decreased relapse rate. This antileukemic mechanism is not well understood. A common finding is the production of short chain fatty acids. Hence, the question of total or selective gut decontamination is discussed controversially. Improved survival was described with the decontamination with rifaximin that is associated with surviving anaerobes and an increased production of indolsulfoxide. Treatment of GVHD of the gut has been attempted with the transfer of stool from a healthy person with some success. This may not only be the beneficial impact of bacteriae, but the composition of bacteriae with phages and other microorganisms. A recent study of the viriome found the presence of picobrna virus associated with GVHD.
The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance.
Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.

Keywords

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" ["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(119) "Hans-Jochem Kolb¹, Daniela Weber², Belinda Pinto Simoes³, Ernst Holler²
" } ["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) "20090" ["VALUE"]=> array(2) { ["TEXT"]=> string(5658) "The role of infections in allogeneic stem cell transplantation and graft-versus-host disease has gained a renewed interest because of several developments in recent years. Variable degrees of immune deficiency exist as a consequence of immune suppression until the immune system of donor origin is established; graft-versus-host disease (GVHD) and immunosuppressive treatment for prophylaxis and therapy may delay the restoration. These conditions favor infections with various microorganisms. Several improvements in prophylaxis and treatment of infections as well as reduced intensity of the conditioning regimens and improved prophylaxis of GVHD have decreased toxicity of the treatment and transplant-related deaths. Improved antibiotics, antiviral and antifungal treatment have contributed to the greater success. However, infections with and without GVHD remain a major obstacle of allogeneic stem cell transplantation and immunotherapy. New diagnostic tools for the study of cytokines released during conditioning, the composition and alteration of the gut microbiome after transplantation and the innate immunity of the gut mucosa have given new insights into the pathophysiology of GVHD. The gut is a primary organ of T cell activation in acute GVHD; the incidence of GVHD is associated with a lower gut microbial diversity. The composition of intestinal microbiota seems to play an important role for the pathophysiology of intestinal GvHD. Commensal bacteria, particularly Clostridiales, like Blautia, have been shown to be associated with less GvHD. The mechanism by which anaerobic bacteria suppress GVHD is still unknown, most likely due to secretion of protective metabolites like short chain fatty acids or indole and its derivatives, thus exerting antiiflammatory effects and contribute to epithelial integrity and immunological homeostasis. Modulation of intestinal microbiota composition may influence the occurrence and severity of gut GvHD. The form of gut decontamination has also an important impact on GVHD. E.g., rifaximin is a broad-spectrum antibiotic with negligible gastrointestinal resorption that spares anaerobic bacteria and improves indoxyl sulfate production. Rifaximin preserves high microbiome diversity upon gut decontamination, as compared to ciprofloxacin and metronidazole being associated with less severe GI GvHD and improved survival. Even kind and timely use of systemic broad-spectrum antibiotics for therapy of neutropenic infections seems to impact gut GvHD. E.g., avoidance of imipenem/cilastatin and piperacillin/tazobactam seems to improve survival by decreasing GVHD rates, probably, due to growth of Akkermannsia muciniphilia with mucus-degrading capabilities, thus, probably, promoting intestinal inflammation and GvHD. Aztreonam and cefipime, both antibiotics with anaerobic sparing effects, may be preferable. Use of antibiotics before the day of transplantation may contribute to severe intestinal dysbiosis and poor outcome of patients after ASCT. The presence of certain strains of anaerobic bacteriae is associated with lower risks of GVHD and relapse of leukemia. Recent studies have shown that gut colonization with some strains of Blautia is associated with lesser risk of GVHD, and strains of Limus (Eubacteriaceae) is associated with a decreased relapse rate. This antileukemic mechanism is not well understood. A common finding is the production of short chain fatty acids. Hence, the question of total or selective gut decontamination is discussed controversially. Improved survival was described with the decontamination with rifaximin that is associated with surviving anaerobes and an increased production of indolsulfoxide. Treatment of GVHD of the gut has been attempted with the transfer of stool from a healthy person with some success. This may not only be the beneficial impact of bacteriae, but the composition of bacteriae with phages and other microorganisms. A recent study of the viriome found the presence of picobrna virus associated with GVHD. The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance. Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs. There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host. <h3>Keywords</h3> Allogeneic hematopoietic cell transplantation, graft-versus-host disease, infection, prevention, gut micro" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5598) "The role of infections in allogeneic stem cell transplantation and graft-versus-host disease has gained a renewed interest because of several developments in recent years. Variable degrees of immune deficiency exist as a consequence of immune suppression until the immune system of donor origin is established; graft-versus-host disease (GVHD) and immunosuppressive treatment for prophylaxis and therapy may delay the restoration. These conditions favor infections with various microorganisms. Several improvements in prophylaxis and treatment of infections as well as reduced intensity of the conditioning regimens and improved prophylaxis of GVHD have decreased toxicity of the treatment and transplant-related deaths.
Improved antibiotics, antiviral and antifungal treatment have contributed to the greater success. However, infections with and without GVHD remain a major obstacle of allogeneic stem cell transplantation and immunotherapy. New diagnostic tools for the study of cytokines released during conditioning, the composition and alteration of the gut microbiome after transplantation and the innate immunity of the gut mucosa have given new insights into the pathophysiology of GVHD. The gut is a primary organ of T cell activation in acute GVHD; the incidence of GVHD is associated with a lower gut microbial diversity.
The composition of intestinal microbiota seems to play an important role for the pathophysiology of intestinal GvHD. Commensal bacteria, particularly Clostridiales, like Blautia, have been shown to be associated with less GvHD. The mechanism by which anaerobic bacteria suppress GVHD is still unknown, most likely due to secretion of protective metabolites like short chain fatty acids or indole and its derivatives, thus exerting antiiflammatory effects and contribute to epithelial integrity and immunological homeostasis. Modulation of intestinal microbiota composition may influence the occurrence and severity of gut GvHD.
The form of gut decontamination has also an important impact on GVHD. E.g., rifaximin is a broad-spectrum antibiotic with negligible gastrointestinal resorption that spares anaerobic bacteria and improves indoxyl sulfate production. Rifaximin preserves high microbiome diversity upon gut decontamination, as compared to ciprofloxacin and metronidazole being associated with less severe GI GvHD and improved survival.
Even kind and timely use of systemic broad-spectrum antibiotics for therapy of neutropenic infections seems to impact gut GvHD. E.g., avoidance of imipenem/cilastatin and piperacillin/tazobactam seems to improve survival by decreasing GVHD rates, probably, due to growth of Akkermannsia muciniphilia with mucus-degrading capabilities, thus, probably, promoting intestinal inflammation and GvHD. Aztreonam and cefipime, both antibiotics with anaerobic sparing effects, may be preferable. Use of antibiotics before the day of transplantation may contribute to severe intestinal dysbiosis and poor outcome of patients after ASCT.
The presence of certain strains of anaerobic bacteriae is associated with lower risks of GVHD and relapse of leukemia. Recent studies have shown that gut colonization with some strains of Blautia is associated with lesser risk of GVHD, and strains of Limus (Eubacteriaceae) is associated with a decreased relapse rate. This antileukemic mechanism is not well understood. A common finding is the production of short chain fatty acids. Hence, the question of total or selective gut decontamination is discussed controversially. Improved survival was described with the decontamination with rifaximin that is associated with surviving anaerobes and an increased production of indolsulfoxide. Treatment of GVHD of the gut has been attempted with the transfer of stool from a healthy person with some success. This may not only be the beneficial impact of bacteriae, but the composition of bacteriae with phages and other microorganisms. A recent study of the viriome found the presence of picobrna virus associated with GVHD.
The gastrointestinal mucosa is an important part of the immune system and there is a delicate equilibrium between the flora itself and the immune surveillance by the host’s immune system. There is a good evidence that the mucosal immune system plays a pivotal role in the development of the patient’s immunity against food antigens and microbial antigens thereby distinguishing between reaction and tolerance.
Viral infections are known to pave the way for subsequent fungal and bacterial infections, but complex interactions between the viruses, bacteria, fungi, nematodes and host mucosa may complicate the picture. A still largely unknown but highly important mechanism of transkingdom control may be associated with poorly studied role of phages that may modulate bacterial colonization. These interactions may be complicated by clinically applied antibiotics (absorbable and non-absorbable), antivirals and other drugs.
There are also some encouraging new ways to prevent and to treat GVHD. Moreover, one may select donors according to their immune repertoire and genetic background for T cell activation. Possibly this can be combined with an anti-leukemic efficiency based on anti-microbial activity and HLA class II DP histocompatibility. In general, the immune activation may be important that is induced by the actual microbiome and determined genetically by the donor and the host.

Keywords

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²Department of Hematology and Oncology, Internal Medicine III, University Medical Center, Regensburg, Germany
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Иммунодефицит различной степени возникает как следствие иммунной супрессии до тех пор, пока не сформируется донорская иммунная система; РТПХ и иммуносупрессивная терапия для профилактики и лечения РТПХ могут вызвать задержку ее восстановления. Эта ситуация способствует инфицированию различными микроорганизмами. Некоторые усовершенствования в профилактике и лечении инфекций, а также снижение интенсивности режимов кондиционирования и улучшение профилактики РТПХ привели к снижению токсичности лечения и смертности, связанной с трансплантацией. Совершенствование терапии антибиотиками бактериальных, а также вирусных и грибковых инфекций внесло свой вклад в развитие этого успеха. Однако инфекции с РТПХ и без нее остаются основным препятствием для алло-ТГСК и иммунотерапии. Новые диагностические средства для исследования цитокинов, выделяющихся в период кондиционирования, состав микробиоты кишечника и ее изменения после ТГСК, а также врожденный иммунитет слизистой кишечника привнесли новый взгляд на патофизиологию РТПХ. Желудочно-кишечный тракт (ЖКТ) является первичным органом активации Т-лимфоцитов при острой РТПХ, и встречаемость РТПХ ассоциирована с меньшим разнообразием микроорганизмов в ЖКТ. Наличие определенных видов анаэробных бактерий ассоциируется со сниженным риском РТПХ и рецидивов лейкоза. Недавние исследования показали, что колонизации ЖКТ некоторыми штаммами Blautia ассоциированы с меньшим риском РТПХ, а ряд линий Limus (Eubacteriaceae) связан со снижением частоты рецидивов. Этот антилейкозный механизм не вполне выяснен. Частой находкой здесь является продукция короткоцепочечных жирных кислот. Таким образом, вопрос о полной или избирательной деконтаминации ЖКТ пока не разрешен. Улучшение выживаемости было описано при деконтаминации рифамиксином, что связывают с выживанием анаэробов и повышенной продукцией индоксилсульфата. Предпринимались попытки лечения РТПХ кишечника путем переноса стула здоровых лиц, что приносило некоторый успех. Это может не только оказывать положительный эффект на бактериальную флору, но и на их взаимодействие с фагами и другими микроорганизмами. Нынешние исследования вирома показали присутствие пикорнавируса, ассоциированного с РТПХ. Слизистая ЖКТ является важной частью иммунной системы, и имеется тонкое равновесие между флорой как таковой и иммунологическим надзором со стороны иммунной системы организма-хозяина. Имеется достаточно доказательств того, что иммунная система слизистых оболочек играет важнейшую роль в развитии иммунного ответа у больных против пищевых антигенов и микробных антигенов, тем самым различая иммунные реакции и иммунную толерантность. Вирусные инфекции, как известно, прокладывают путь для последующих грибковых и бактериальных инфекций, но сложные взаимодействия между вирусами, бактериями грибками, нематодами и слизистой оболочкой могут осложнять общую картину. До сих пор во многом не ясно, насколько важен взаимный контроль различных царств микробиоты и он может быть связан с малоизученной ролью бактериофагов которые могут модулировать микробную колонизацию. Эти взаимодействия могут осложняться применением в клинике абсорбируемых и неабсорбируемых антибиотиков, антивирусных и других препаратов. Есть и некоторые перспективные способы предотвращения и лечения РТПХ. Так, можно выбирать доноров в соответствии с их иммунным репертуаром и генетическим фоном для активации Т-клеток. Возможно, этот подход может сочетаться с антилейкемическим эффектом, основанным на антимикробной активности и тканевой совместимости по HLA (класс II DP-гены). 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Ключевые слова

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Регенсбург, Германия
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Introduction

Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) is considered an integral component of most treatment protocols aimed for therapy of hematological malignancies and solid tumors as well as some genetic diseases in children and adolescents. It is a method of choice for the patients with non-malignant clinical conditions intended for correction of inherited deficiency typical to the given syndrome, repopulation of the immune system by normal cells, or replenishment of a deficient enzyme, e.g., in storage diseases [1, 2]. Choosing an optimally compatible donor is a key factor determining favorable outcome in HSCT [3]. An HLA-compatible unrelated donor is not available for ca. 15-20% of the patients, because of extreme allelic variability of HLA system. Lower HLA compatibility is associated with additional risks of severe posttransplant immune complications, e.g., graft-versus-host disease. Pharmacological prevention of acute GVHD is based on combined usage of different medications, i.e., calcineurin inhibitors, cytostatic drugs (metothrexate, micophenolate mophetyl), m-TOR inhibitors, antithymocyte immunoglobulins. Cyclophosphamide at early terms post-transplant (days +3+4) is considered as a novel approach to aGvHD prophylaxis after HSCT (PTCy). The mean purpose of this therapy is to abrogate effects of activated alloreactive T lymphocytes, thus allowing to decrease acute GVHD risk by 30%. However, most published data describes treatment of adult patients with hematological malignancies [5, 6], several studies in pediatric HSCT are also based on this category of patients. Hence, the aim of the present study was to assess efficiency of PTCy therapy in pediatric patients with non-malignant diseases.

Patients and Methods

Over the time period of 2005 to March 2018, we observed ninety-seven patients with various non-malignant diseases subjected to allo-HSCT at the clinic of R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation. A total of 118 allo-HSCT were performed including 21 cases (18%) of repeated transplants, due to initial graft failure, or secondary rejection. The primary non-malignant conditions were represented by the following disorders: hemoglobinopathies, 8 patients (8%); bone marrow insufficiency (both inborn and acquired), 44 cases (46%); metabolic diseases, 35 cases (36%), primary immune deficiencies, 10 patients (10%).
Acute GVHD (aGVHD) prophylaxis in majority of HSCT cases was based on calcineurin inhibitors (n=89, 75%). Posttransplant cyclophosphamide (PtCy) was administered in 29 cases (25%), at the dose of 50 mg/kg weight (days +3 and +4 after HSCT). This schedule of GVHD prophylaxis was most often in type 1 mucopolysaccharidosis (Hurler syndrome) (n=9), beta-thalassemia (n=9). In 11 cases (38%), HSCT was performed from haploidentical donors, or as a repeated transplant (n=9, 31%). Myeloablative and reduced-intensity conditioning regimens were applied at similar rates (respectively, for 15 and 14 cases).

Results

The two-year survival rates in total group did not substantially differ between standard GVHD prophylaxis schedule, and the PtCy protocol (62% versus 64%) (Fig. 1А). A number of factors did sufficiently improve this parameter: patient’s age (under 5 years old) by the moment of HSCT (77% vs 50%, р=0.004, see Fig. 1B); shorter time period (under 2 years) from diagnosis to allo-HSCT (74% vs 47%, р=0.003,see Fig. 1C), transplant engraftment (72% vs 44%, р=0.001, see Fig. 1D).
Successful engraftment was documented in 91 cases. Cumulative engraftment rates did not differ between the groups with standard protocol and PtCy prophylaxis (70% vs 84%, see Fig. 2А). Likewise, we have not revealed any significant differences for the groups treated according to MAC and RIC schedules (87.5% vs 77%, р=0.31, see Fig. 2B). However, the patients subjected to non-myeloablative conditioning followed by Cy treatment showed a definitely lower engraftment rate (86 vs 50%, р=0.004, see Fig. 2C).
Stem cell engraftment in our patients was dependent on the donor type. I.e., the patients who underwent HSCT from HLA-compatible donor (either related or unrelated) showed higher engraftment frequency than the patients who have got stem cells from haploidentical donor (92% vs 84% vs 58%, р=0.05, see Fig. 3).
The primary disease for which allo-HSCT was performed was also of importance. E.g., the patients with primary immune deficiencies demonstrated engraftment in all cases. The lowest engraftment rate was observed in patients with hemoglobinopathies. Functioning graft among the patients who received second HSCT due to failure of the first transplant, was achieved in only 46% of cases.
Cumulative incidence (CI) of aGVHD rate in post-HSCT patients was 32% of total. The patients with PtCy had lower CI aGVHD if compared to the group with standard prophylaxis (26% vs 47%, р=0.05, Fig. 4А). CI of aGVHD with skin affection was also significantly lower in the PtCy group (23% vs 45%, р=0.046) as seen from the Fig. 4B. Intestinal and hepatic aGVHD occurred in the both groups at comparable rates. The inter-group distribution for severity grade was also similar.
Clinical results of PtCy treatment were specially evaluated for the most homogenous group of the patients with Hurler syndrome (type 1 MPS). This cohort was represented by 22 allo-HSCT, with PtCy prophylaxis in six cases. Overall survival was similar for the patients subjected to different aGVHD prophylaxis (82% at standard aGVHD prophylaxis versus 100% in PtCy group, see Fig. 5А). Clinical engraftment was achieved in all cases, whereas CI of aGVHD was 63% in the standard prophylaxis group against 34% for the PtCy group (Fig. 5B). Frequency of life-threatening GVHD (stage III to IV) did not differ significantly (20% versus 18%, Fig. 5C).

28-35 figure 1-2.png

28-35 figure 1-2 (1).png

Table 1. Primary clinical conditions in the patients with non-malignant disorders.png

Table 2. Demographic and clinical characteristics of the patients subjected to acute GVHD prophylaxis based.png

Table 3. aGVHD frequency and distribution by severity for the groups with standard (calcineurin inhibitor-based).png

Figure 3. Cumulative engraftment rate (ordinate) in the.png

Figure 4. (A) Total CI of aGVHD (ordinate); (B) CI of skin aGVHD among the patients subjected to standard GVHD.png

Figure 5. (А) Overall survival among patients with.png

Discussion

Search for a fully HLA-matched donor for HSCT is critical to the patients with non-malignant diseases. Due to ethnic background of the patients with thalassemia, autosomal recessive osteopetrosis etc., they are unlikely to find a compatible donor. Time is also an important factor, especially for the patients with primary immune deficiencies or storage metabolic diseases which extends the prospective for recruitment of alternative stem cell donors [7]. Allo-HSCT from a nonrelated donor or partially compatible haploidentical donor exhibit comparable survival parameters for the patients with non-malignant disorders. Under these conditions, the PtCy-based GHD prophylaxis provides good control of evolving aGVHD [8]. A higher risk of non-engraftment in cases of haploidentical donorship could be decreased due to myeloablative conditioning regimens. The recruitment of haploidentical donors for HSCT in children with primary immune deficiencies and sickle-cell anemia have been described in present studies [9, 10, 11]. PtCy prophylaxis was applied in all these cases showing its clinical efficiency. This approach has additional benefits when applying peripheral blood stem cells as a source of transplant [8, 12].

Conclusion

aGVHD prevention based on cyclophosphamide prophylaxis is an effective treatment which may decrease risk of aGVHD specially in skin affection when compared to standard treatment methods based on calcineurin inhibitors. However, higher non-engraftment rate can be a potential hazard of HSCT performed in patients with non-malignant disorders when using non-myeloablative conditioning regimens and PtCy-based GVHD prophylaxis.

Conflict of interest

No conflicts of interest are reported.

References

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2. Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: current issues and prospectives. Russian J Pediatric Hematol Oncol. 2015; 2(2): 28-42 (In Russian).

3. Afanasyev BV, Zubarovskaya LS, Alyansky AL. Paina OV, Borovkova AS, Kuzmich EV, Bykova TA, Deev RV, Isaev AA. Donor selection in allogeneic hematopoietic stem cell transplantation. Russian J Pediatric Hematol Oncol. 2016; 3(3): 30-36 (In Russian).

4. Owens AH, Santos GW. The effect of cytotoxic drugs on graft-versus-host disease in mice. Transplantation. 1971. 4(11): 378–382.

5. Moiseev IS, Pirogova OV, Babenko EV, Gindina TL, Darskaya EI, Morozova EV, Bondarenko SN, Afanasyev BV. Single-agent post-transplantation cyclophosphamide versus calcineurin-based graft-versus-host disease prophylaxis in matched related bone marrow transplantation. Cell Ther Transplant. 2017; 6(4): 52-59.

6. Moiseev IS, Pirogova OV, Alyanski AL, Babenko EV, Gindina TL, Darskaya EI, Slesarchuk OA, Bondarenko SN, Afanasyev BV. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Biol Blood Marrow Transplant. 2016; 22(6):1037-1042.

7. Booth C, Silva J, Veys P. Stem cell transplantation for the treatment of immunodeficiency in children: current status and hopes for the future. Expert Rev Clin Immunol. 2016;12(7):713-723.

8. Jaiswal SR, Chakrabarti A, Chatterjee S, Ray K, Chakrabarti S. Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children. Pediatr Transplant. 2016;20(5):675-82.

9. Rastogi N, Katewa S,Thakkar D, Kohli S, Nivargi S,Yadav SP. Reduced-toxicity alternate-donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders. Pediat Blood Cancer. 2018;65(1). doi: 10.1002/pbc.26783.

10. Thakkar D, Katewa S, Rastogi N, Kohli S, Nivargi S, Yadav SP. Successful reduced intensity conditioning alternate donor stem cell transplant for Wiskott-Aldrich syndrome. J Pediat Hematol Oncol. 2017;39(8):e493-e496.

11. Wiebking V, Hütker S, Schmid I, Immler S, Feuchtinger T, Albert MH. Reduced toxicity, myeloablative HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for sickle cell disease. Ann Hematol. 2017;96(8):1373-1377.

12. Jaiswal SR, Chakrabarti A, Chatterjee S, Ray K, Chakrabarti S. Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children. Pediatr Transplant.2016;20(5):675-682.

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Introduction

Patients and Methods

Results

28-35 figure 1-2.png

28-35 figure 1-2 (1).png

Table 1. Primary clinical conditions in the patients with non-malignant disorders.png

Table 2. Demographic and clinical characteristics of the patients subjected to acute GVHD prophylaxis based.png

Table 3. aGVHD frequency and distribution by severity for the groups with standard (calcineurin inhibitor-based).png

Figure 3. Cumulative engraftment rate (ordinate) in the.png

Figure 4. (A) Total CI of aGVHD (ordinate); (B) CI of skin aGVHD among the patients subjected to standard GVHD.png

Figure 5. (А) Overall survival among patients with.png

Discussion

Conclusion

Conflict of interest

No conflicts of interest are reported.

References

4. Owens AH, Santos GW. The effect of cytotoxic drugs on graft-versus-host disease in mice. Transplantation. 1971. 4(11): 378–382.

7. Booth C, Silva J, Veys P. Stem cell transplantation for the treatment of immunodeficiency in children: current status and hopes for the future. Expert Rev Clin Immunol. 2016;12(7):713-723.

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Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития. <h3 style="text-align: justify;">Цель работы</h3> Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами. <h3 style="text-align: justify;">Пациенты и методы</h3> В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4. <h3 style="text-align: justify;">Результаты</h3> Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004). <h3 style="text-align: justify;">Заключение</h3> Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. 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Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития.

Цель работы

Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами.

Пациенты и методы

В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4.

Результаты

Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004).

Заключение

Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом.

Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes.

Patients and Methods

97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4.

Results

Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis.

Keywords

Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis.

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Bykova, Anastasia S. Borovkova, Anna A. Osipova, Varvara N. Ovechkina, Olesya V. Paina, Polina V. Kozhokar, Alexander L. Alyanskyi, Alexander D. Kulagin, Elena V. Semenova, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. Afanasyev " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(250) "Tatiana A. Bykova, Anastasia S. Borovkova, Anna A. Osipova, Varvara N. Ovechkina, Olesya V. Paina, Polina V. Kozhokar, Alexander L. Alyanskyi, Alexander D. Kulagin, Elena V. Semenova, *Boris I. Smirnov, Ludmila S. Zubarovskaya, 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(250) "Tatiana A. Bykova, Anastasia S. Borovkova, Anna A. Osipova, Varvara N. Ovechkina, Olesya V. Paina, Polina V. Kozhokar, Alexander L. Alyanskyi, Alexander D. Kulagin, Elena V. Semenova, *Boris I. Smirnov, Ludmila S. Zubarovskaya, 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) "20116" ["VALUE"]=> array(2) { ["TEXT"]=> string(2521) " Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes. <h3 style="text-align: justify;">Patients and Methods</h3> 97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4. <h3 style="text-align: justify;">Results</h3> Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis. <h2 style="text-align: justify;">Keywords</h2> Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2367) "

Patients and Methods

Results

Keywords

Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis.

Patients and Methods

Results

Keywords

Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis.

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Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology; Department of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia *The St. Petersburg State Electrotechnical University (LETI), 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(327) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology; Department of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia *The 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" } ["DISPLAY_VALUE"]=> string(327) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology; Department of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. 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Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(429) "Татьяна А. Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, 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" } ["DISPLAY_VALUE"]=> string(429) "Татьяна А. Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, 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) "20112" ["VALUE"]=> array(2) { ["TEXT"]=> string(4727) " Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития. <h3 style="text-align: justify;">Цель работы</h3> Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами. <h3 style="text-align: justify;">Пациенты и методы</h3> В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4. <h3 style="text-align: justify;">Результаты</h3> Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004). <h3 style="text-align: justify;">Заключение</h3> Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ. <h2 style="text-align: justify;">Ключевые слова</h2> Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4485) "

Цель работы

Пациенты и методы

Результаты

Заключение

Ключевые слова

Цель работы

Пациенты и методы

Результаты

Заключение

Ключевые слова

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Introduction

Parvovirus B19 (PVB19) is a well known small DNA virus from Erythrovirus genus which is in scope of pediatricians for decades being associated with erythropoiesis disturbances, arthropathies, myocarditis and other disabling clinical conditions [1]. PVB19 shows an affinity for the group P antigen of red blood cells, with lesser amounts in blood plasma [2]. The major hematotoxic effect of the virus is believed to occur at the pronormoblast stage, thus causing arrest of erythroid differentiation. PVB19 was occasionally found in aplastic anemias and pure red cell aplasia [3]. In this respect, most studies concerned resistant anemia cases in the patients subjected to renal transplantation where the PVB19 was not a rare finding [4].
Over past years, many cases of severe myocarditis and hepatitis were shown to be associated with parvovirus infection, as based on positive PVB19 antigen or DNA findings in affected tissues. Meanwhile, a latent persistence of PVB19 was quite common in skin, synovial tissues, myocardium and bone marrow [5]. The viral DNA was detectable in peripheral blood from 5% of healthy donors [6]. The authors suggest only a small risk for the donor-recipient viral transmission upon hematopoietic stem cell transplantation (HSCT).
Following allogeneic HSCT, a regular activation of herpesviruses and other latent pathogens is observed, due to acute myelosuppression and cellular immune deficiency [7]. Clinical significance of the PVB19 in immunocompromised patients is not yet properly evaluated. E.g., a prolonged study of the PVB19 viral load has been performed in 53 patients after allo-HSCT using quantitative PCR [8]. Specific viral DNA was detectable in blood serum from 30% of the HSCT recipients, either before, or after HSCT, at maximal viral load observed 2 months post-transplant. However, the patients with detectable PVB19 did not show specific clinical symptoms that could be ascribed to parvovirus infection.
Hence, the aim of our work was to compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels, and rates of hematopoietic recovery within 60 days after allo-HSCT. Our preliminary data point to a prognostic significance of parvovirus DNA detection and increased antibody levels is possible predictors for delayed engraftment and febrile neutropenia.
36-43 Table 1. Clinical and demographic characteristics of the patients at allo-HSCT.png

Patients and Methods

A total of 54 pediatric and adolescent patients were involved into the study at the median age of 7.2 (0.6 to 19 years old), who had a malignant disease of hematopoiesis or inherited disorders as initial diagnosis who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-one patient of this group were observed for at least 2 months (60 days) after HSCT. Selection of the patients for allo-HSCT, choice of conditioning regimens, prophylaxis of acute graftversus-host disease was performed according to current EBMT recommendations. Most part of this group was represented by the patients with acute myeloblastic leukemia (AML, n=16; 30%), acute lymphoblastic leukemia (ALL, n=14; 26%); severe anemias (SAA) of different origin (13%; n=7). 33% of the patients were in first remission after previous treatment. Socio-demographic features their distribution for diagnosis and stage of the disease, main parameters of allo-HSCT, are shown in Tables 1 and 2.
Bone marrow was used as a source of hematopoietic stem cells in 83% of cases (45 of 54 patients), infusion of peripheral stem cells was applied in the rest of cases. Allo-HSCT from unrelated donors was performed in 45% of cases (24 of 54); grafting from matched related donors or haploidentical transplant was carried out in, resp., 20% (11/54) and 35%(19/54) patients. Reduced-intensity conditioning was used in nearly all cases (51 of 54 patients). Development of acute GvHD within early period after allo-HSCT was observed in 25 patients, of them, 9 exhibited grade 3-4 GvHD. Regular examination of the patients before and after HSCT was carried out according to a standard local clinical protocol. He study was approved by the Local Institutional Board at the St.Petersburg State I. Pavlov Medical University. The laboratory studies included routine blood counts and serum biochemistry, urinalysis etc. Quantitative determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) in blood plasma was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. DNA extraction from the samples and quantitative evaluation of PVB19 DNA in the samples were performed by means of PCR with specific fluorescent probes using “Ampliprime” amplification kits» and «Amplisens® Parvovirus В19-FL» (Moscow, Russia). Moreover, quantitative determination of IgМ and IgG antibodies to PV B19 was performed by means of ELISA at 0, +30 and +60 days post-transplant using «Anti-Parvovirus B19 ELISA IgМ» and «Anti-Parvovirus B19 ELISA IgG» kits (EUROIMMUN, Germany). The diagnostic kits were used according to instruction. Statistical evaluation of the data was performed with a Winstat software package.
Table 2. Main characteristics of allogeneic HSCT in the group under study.png

Results

Transplant-related changes of PVB19 DNA levels and anti-PVB19 antibodies

The pre-transplant contents of PVB19 DNA and IgG antibodies to the virus showed a broad-range scatter (Table 3). PVB19 was found in about 30% of this group. Meanwhile, 68% of the patients exhibited increased levels of IgG-anti- PVB19 antibodies (>10 IU/ml), thus reflecting high prevalence of adaptive immune response. Mean pre-transplant contents of PVB19 DNA did not correlate either with age of the patients, or with clinical disease status, physical state, or activation of other latent viruses.
The detectability and average levels of PVB19 DNA as well as concentrations of anti-PVB19 antibodies did not show any significant changes at 30 or 60 days after HSCT, as seen from Table 1. However, actual scatter of these data proved to be rather sufficient, thus suggesting some correlations between these laboratory indexes and clinical signs in the individual patients. In particular, positive (non-zero) viral loads have been registered in 28% before allo-HSCT, 29% and 30.4% on day+30 and day+60 after allo-HSCT, i.e., ca 70% of the patients showed negative results for PVB19 over the early period after allo-HSCT.

Association between the PVB19 presence and specific antibody response after allogeneic HSCT

Detection of PVB19 DNA, both before and after allo-HSCT was not accompanied by IgM antibody detection at any observation point, thus suggesting absence of acute infectious process caused by parvovirus infection.
Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p=8x10-6, 153 assays in 54 clinical cases). In particular, a significant correlation was shown between initial viral load and anti-PVB19 levels at all three terms of the study (Table 3) being, however, maximal at the day+60 after allo-HSCT.
Table 3. Mean and median values for serum IgG PVB19 antibodies and specific viral DNA before and at different terms.png
As seen from Fig. 1, a significant correlation exists between pre-transplant PVB19 load and expressed antibody response detected 60 days after allo-HSCT, i.e., the non-zero viral loads were associated with higher contents of specific antibodies, thus suggesting an association between the PVB19 persistence and production of virus-specific antibodies (Fig. 1).
A half-life time for endogenous IgG antibodies in humans is about 1 to 4 weeks [10]. These findings suggest an opportunity of specific antibody production at early terms after intensive cytostatic treatment, due to potential activity of surviving memory cells, e.g., plasmocytes which are able to function for months and even years after their maturation.

Parvovirus В19 activation and hematopoiesis recovery

In our clinical series, altered engraftment was, generally, more common at increased IgG PVB19 antibody levels when determined 60 days after HSCT (r=0.315; p=0.034; n=46).
Specifically, significant correlations were shown between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels (Fig. 2-4). This association may suggest a relation between continued parvovirus persistence and slower hematopoiesis recovery at 30 to 60 days post-transplant.
In general, altered engraftment was also registered in cases with higher IgG antibodies against parvovirus 60 days after HSCT (r=0.315; p=0.034; n=46).

Parvovirus detection and febrile neutropenia

Positivity for PVB19 DNA by the day +30 after allo-HSCT was, in all cases (14/14), associated with febrile neutropenia (FN), as compared to 68% in patients with nondetectable PVB19 (23/34; р=0.015, see Table 4). Hence, active parvovirus infection could be a sufficient factor of common febrile reactions observed in early posttransplant neutropenia, thus supporting pathogenic significance of this infection, at least, in a subgroup of immunocompromised patiens. Development of these febrile responses could be either virus-induced, or combined with secondary bacterial infections caused by slow recovery of cellular immunity.

Discussion

The issue of optimal PVB19 diagnostics in heavily treated hematological patients is not yet clear, since the results of serological tests (serum IgM and IgG antibodies) did not correlate with detection of viral DNA in blood serum or bone marrow from the HSCT recipients [9]. In our study, a pilot group of the HSCT patients was studied for PVB19 DNA and specific serum antibodies before and at 30-60 days following transplantation. Generally, PVB19 was found at, generally, in about 30% of this group. Remarkably, these figures were at rather low levels, both pre-transplant and after HSCT and did not sufficiently increase post-translant. Mean initial concentrations of PVB19 DNA did not correlate either with age of the patients, or with clinical disease status, physical state, or activation of other latent viruses. IgM antibodies to PVB19 were not detectable in HSCT patients, thus suggesting absence of de novo infection. However, class IgG antibodies(>10 IU/ml) were, found in ca 70% of cases thus presuming previous contacts with the virus. Hence, the background levels of parvovirus exist both pre- and posttransplant.
A search for associations between PVB19 positivity and specific antibody production have shown a significant correlation between pre-transplant PVB19 load and expressed IgG antibody response detected 60 days after allo-HSCT, i.e., the non-zero viral loads were associated with higher contents of specific antibodies, thus suggesting an association between the PVB19 persistence and production of virus-specific antibodies.

Conclusions

1. Presence of parvovirus B19 in peripheral blood of children before allogeneic hematopoietic stem cell transplantation is followed by increased PV-specific antibodies of IgG class in blood serum at all terms after allo-HSCT.
2. Increased IgG levels of antibodies in blood of the patients after allo-HSCT is associated with relative neutropenia and thrombocytopenia at first 2 months after allo-HSCT.
3. Detection of parvovirus DNA at initial terms (before HSCT) and and 30-60 days later may be followed by development of early febrile neutropenias and slower recovery oferythrocyte and platelet counts in peripheral blood.
Table 4. Differences in PVB19 levels for the patients with vs without febrile neutropenia (p=0.015).png
figure 1-2.png

Conflict of interest

The authors report no conflicts of interest.

References

1. Asano Y, Yoshikawa T. Human herpesvirus-6 and parvovirus B19 infections in children. Curr Opin Pediatr. 1993;5(1):14-20.
2. Lee TH, Kleinman SH, Wen L, Montalvo L, Todd DS, Wright DJ, Tobler LH, Busch MP; NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II). Distribution of parvovirus B19 DNA in blood compartments and persistence of virus in blood donors. Transfusion. 2011;51(9):1896-908.
3. Urban C, Lackner H, Müller E, Benesch M, Strenger V, Sovinz P, Schwinger W. Stem cell transplantation in 6 children with parvovirus B19- induced severe aplastic anaemia or myelodysplastic syndrome. Klin Pädiatr. 2011;223(6):332-334.
4. Egbuna O, Zand MS, Arbini A, Menegus M, Taylor J. A cluster of parvovirus B19 infections in renal transplant recipients: a prospective case series and review of the literature. Am J Transplant. 2006;6(1):225-231.
5. Corcioli F, Zakrzewska K, Rinieri A, Fanci R, Innocenti M, Civinini R, De Giorgi V, Di Lollo S, Azzi A. Tissue persistence of parvovirus B19 genotypes in asymptomatic persons. J Med Virol. 2008;80(11):2005-2011.
6. Gama BE, Emmel VE, Oliveira-Silva M, Gutiyama LM, Arcuri L, Colares M, de Cássia Tavares R, Bouzas LF, Abdelhay E, Hassan R. Parvovirus B19 in the Context of Hematopoietic Stem Cell Transplantation: Evaluating Cell Donors and Recipients. Transplant Direct. 2017;3(11):e217. doi:10.1097/TXD.0000000000000731.
7. Pankratova OS, Chukhlovin AB. Time course of immune recovery and viral rwactivation following hematopoietic stem cell transplantation. Cell.Ther Transplant. 2016; 5(4):32-43.
8. Rahiala J, Koskenvuo M, Norja P, Meriluoto M, Toppinen M, Lahtinen A, Väisänen E, Waris M, Vuorinen T, Saarinen-Pihkala U, Lappalainen M, Allander T, Ruuskanen O, Hedman K, Söderlund-Venermo M, Vettenranta K. Human parvoviruses B19, PARV4 and bocavirus in pediatric patients with allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48(10):1308-1312.
9. Lundqvist A, Tolfvenstam T, Brytting M, Stolt CM, Hedman K, Broliden K. Prevalence of parvovirus B19 DNA in bone marrow of patients with haematological disorders. Scand J Infect Dis. 1999;31(2):119-122.
10. Kontermann RE. Strategies to extend plasma half-lives of recombinant antibodies. Biodrugs. 2009; 23(2): 93-109.

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Introduction

Patients and Methods

Results

Transplant-related changes of PVB19 DNA levels and anti-PVB19 antibodies

Association between the PVB19 presence and specific antibody response after allogeneic HSCT

Parvovirus В19 activation and hematopoiesis recovery

Parvovirus detection and febrile neutropenia

Discussion

Conclusions

Conflict of interest

The authors report no conflicts of interest.

References

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Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА. Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК. Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций. В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК. <h2 style="text-align: justify;">Ключевые слова</h2> Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения. 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["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) "20122" ["VALUE"]=> array(2) { ["TEXT"]=> string(221) "Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, Борис В.Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(221) "Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, 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) "20123" ["VALUE"]=> array(2) { ["TEXT"]=> string(465) "НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия; НИИ детской онкологии, гематологии и Трансплантологии им. Р. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, 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(465) "НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия; НИИ детской онкологии, гематологии и Трансплантологии им. Р. 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) "20124" ["VALUE"]=> array(2) { ["TEXT"]=> string(5888) " Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА. Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК. Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций. В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК. <h2 style="text-align: justify;">Ключевые слова</h2> Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5796) "

Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.
Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.
Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.
В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения.

Parvovirus B19 (PVB19) is a well known DNA virus which seems to be associated, e.g., with erythropoiesis disturbances. Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method.

Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (>10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT.

Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p<0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections.

Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT.

Keywords

Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia.

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Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method. Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (>10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT. Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p<0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections. Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT. <h2 style="text-align: justify;"> Keywords</h2> Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3204) "

Keywords

Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia.

Keywords

Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia.

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Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, 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(266) "L. Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, 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(266) "L. Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, 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) "20122" ["VALUE"]=> array(2) { ["TEXT"]=> string(221) "Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, Борис В.Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(221) "Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, 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" } ["DISPLAY_VALUE"]=> string(221) "Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, 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) "20124" ["VALUE"]=> array(2) { ["TEXT"]=> string(5888) " Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА. Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК. Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций. В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК. <h2 style="text-align: justify;">Ключевые слова</h2> Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5796) "

Ключевые слова

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Introduction

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases with abnormalities in hematopoietic stem cells, which is based on somatic mutations of various genes and/or alterations in epigenetic regulation induced by disturbance of the microenvironment, as well as disturbances in the immune system of antitumor surveillance. In many patients, the development of MDS is preceded by a period of non-clonal or clonal cytopenia of an unclear significance, which is induced by somatic mutations associated with age and an increased risk of leukemia. This results in increased proliferation, inefficiency of clonal hematopoiesis and suppression of normal hematopoiesis, and in advanced stages in an abrogation of differentiation, accumulation of blasts and the risk of transformation into acute leukemia.
The incidence of MDS increases markedly with age and the disease is most prevalent in individuals who are white and male. It is conservatively estimated that >10,000 new cases of MDS occur annually, and that ≥60,000 individuals with MDS currently reside in the United States [1].
Recent studies have provided consistent evidence of age-related hematopoietic clones (clonal hematopoiesis of indeterminate potential; CHIP) [2], driven by mutations of genes that are recurrently mutated in myeloid neoplasms and associated with increase in the risk of hematologic cancer. Although several issues remain to be clarified, targeted gene sequencing may be of potential value in the dissection between clonal myelodysplasia, nonclonal cytopenia, and clonal hematopoiesis arising upon aging or in the context of acquired marrow failure [3].
A distinctive feature of both MDS and a number of related diseases (MDS/myeloproliferative tumors, secondary acute myeloid leukemia) is an alteration in DNA methylation processes [4]. Currently, hypomethylating agents (HMA: 5-azacytidine and decitabine) are the only approved medications for the treatment of MDS [5, 6], but only 40-50% of patients respond to therapy [7]. Though there is relatively favorable cytogenetic subset of patients bearing 5q deletion with high initial response rate to lenalidomide, 35% of them will not respond to or do not tolerate the drug. Moreover, most of these patients will lose their response after a few years, requiring switching to HMA as one of further treatment options [8].
Existing prognostic factors regarding survival and the likelihood of response to therapy are based largely on the results of morphological and cytogenetic studies [9]. At the moment, their predictive power is insufficient to make a clinical decision regarding the rationale for therapy with HMA [10]. In connection with these problems, the search for biomarkers, which have prognostic significance with respect to survival and individual response to treatment, is ongoing. The use of modern tools of genome research allowed taking a fresh look at the pathogenesis of MDS and related diseases. Genes involved in both methylation and other metabolic pathways are often mutated with MDS [11]. At the moment, a number of works have been published that analyze the mutational status of the main genes involved in the pathogenesis of MDS and their predictive value in the context of response to therapy and overall survival.
The main goal of our study was to compare the data on the frequency of mutations in different populations of patients with MDS. We also conducted a meta-analysis combining data from available studies to systematically assess the impact of mutation status on response and survival.

Materials and methods

Data collection

The electronic literature search was conducted in the Pub-Med and Cochrane database. Studies were selected if they enrolled patients with various forms of MDS, as well as MDS/myeloproliferative tumors, which underwent first-line therapy with hypomethylating agents. An additional prerequisite was the fact that these studies performed full-genomic or full-exome sequencing in order to identify somatic mutations having prognostic significance with respect to overall survival and/or response to therapy. The search terms were “myelodysplastic syndrome” “sequencing” “patients” and “azacitidine”/”decitabine”. Only articles in English were included in the analysis (Fig. 1). According to these criteria, 12 original articles were selected (Table 1), from which primary data were extracted, which served as the basis for the combined database of this study. Mutation frequencies in the following genes were included in the combined database: ASXL1, DNMT3A, EZH2, U2AF1, TET2, RUNX1, TP53, SRSF2, RAS, SF3B1, CBL (Table 2).
44-51 Table 1.The list of studies used for data analysis.png
44-51 Table 2. Number of patients in whom the gene.png

Statistical analysis

The meta-analysis included the studies with available individual mutational status along with response to HMA and/ or survival data. Based on this information a surrogate table was re-created with nominal variables. The interstudy difference in the prevalence of mutations as well as the response to therapy was analyzed with chi-square test based on the created surrogate tables. The survival variable was treated as logical and non-time dependent due to absence of individual time data. Confidence intervals for the incidence of mutations were calculated based on individual incidences in the studies with random effect model. The confidence intervals for response and survival were produced based on mixed models. The heterogeneity between studies was assessed with Cochran’s Q test with n degrees of freedom. The studies with lees then ten patients per mutation were excluded from the heterogeneity analysis. The analysis was performed in SAS 9.3. The significance for all tests was set at 0.05.

Results

Frequency of mutations in the studied population

We observed a statistically significant difference in the frequencies of all the mutations studied, depending on the study population (for specific studies see Fig. 1). Mean frequency and 95%CI for each mutation were as follows: ASXL1 22.5% (13.6-29.8%); DNMT3A 10.7% (7.3-12.9%); EZH2 5.3% (2.4-7.0%); U2AF1 9.5% (3.7-13.8%); TET2 21.3% (14.2-32.5%); RUNX1 9.1% (3.9-13.7%); TP53 9.4% (4.7-15.2%); SRSF2 13.6% (7.1-28.1%); RAS 4.9% (2.2-15.1%); SF3B1 12.0% (4.4-12.2%); CBL 3.2% (0.1-8.9%); None 18.2% (8.0-23.3%); р<0.0001.
44-51 Figure 2. The inter-study differences for the incidence.png

Response to HMA and overall survival associated with presence of specific mutations

The simulation of common incidence table across studies demonstrated a statistically significant effect on the frequency of response to therapy for mutations in ASXL1, DNMT3A, TET2, RUNX1, TP53, SRSF2, SF3B1 genes and for patients without corresponding mutations (Fig. 3A, 4A). Mean response rates and 95%CI for each mutation were: ASXL1 50.2% (48.8-51.6%); DNMT3A 50.4% (48.3-52.5%); EZH2 49.6% (47.3-51.9%); U2AF1 49.7% (48.2-51.2%); TET2 50.6% (49.3-51.9%); RUNX1 49.6% (47.8-51.4%); TP53 52.0% (48.7-55.2%); SRSF2 51.0% (48.5-53.6%); RAS 50.9% (36.9-64.7%); SF3B1 50.3% (48.5-52.1%); CBL 49.0% (44.9-53.1%); None, 50.3% (47.7-52.8%).
A statistically significant effect on the level of survival for mutations in the genes ASXL1, DNMT3A, EZH2, U2AF1, TET2, RUNX1, TP53, SF3B1, CBL was revealed (Fig. 3B, 4B). Mean overall survival and 95%CI for each mutation were: ASXL1 49.5% (47.2-51.8%); DNMT3A 48.7% (45.6-51.9%); EZH2 49.1% (42.9-55.5%); U2AF1 49.0% (43.0-55.1%); TET2 48.8% (46.7-51.0%); RUNX1 49.0% (45.9-52.1%); TP53 46.8% (44.0-49.7%); SRSF2 51.3% (43.5-59.0%); SF3B1 50.4% (47.0-53.8%); CBL 48.7% (45.5-51.8); None, 52.6% (10.0-91.7%).
However, the magnitude of difference both in response and in survival was relatively modest. For example, the mean OS for DMT3A and TET2 were 48.7% and 48.8%, respectively. Another example of close incidences of responses: 52.0% and 50.2% for patients with TP53 and TET2 mutations, respectively.
Mutations in CBL, EZH2, U2AF1, RAS genes didn’t produce any significant effect on response rate as well as there was no significant impact on survival observed for SRSF2 mutation and in patients without any corresponding mutations.
Fig. 4 contains the forest plot showing mean effects of different gene mutations upon drug response, overall survival, and appropriate confidence intervals.
44-51 Figure 3. Frequency of response to the HMA therapy.png

Discussion

The identification of MDS patients with a high probability of response to HMA therapy remains an important and unresolved clinical task. From the available data, it is known that the presence of a number of somatic mutations can affect the response rates to therapy and the level of overall survival [12]. Mutations in the TET2, DNMT3A, TP53 genes were reported to be associated with a high probability of response to HMA [13, 14, 15]. At the same time, mutations in the EZH2 and TP53 genes are associated with a lower level of overall survival [11, 13]. However these findings are not confirmed in the other studies [11, 15]. Thus it is crucial to understand the reasons behind the variability of results.
In this study we summarized the results of 12 studies with whole exome/genome sequencing in MDS [10, 11, 13-22]. The main difference in this meta-analysis is the availability of individual patient data, thus we have not merged the confidence intervals and response rates, but re-created the interstudy database with mutations, response to therapy and survival. This approach allowed calculating very precise incidence of the mutations and confidence intervals on more than one thousand patients. The obvious weakness of the study is the absence of clinical risk stratification, longitudinal follow-up as well as duration and depth of the response.
One of the first important conclusions of this study is the significant heterogeneity in the incidence of mutations across studies. On the one hand, this might be due to heterogeneity in the age, gender, risk of the disease and high percentage of chronic myelomonocytic leukemia in several studies [18, 21]. On the other hand, the 2012 World Health Organization survey, revealed substantial difference in the incidence of blood cancer across the globe [23]. Thus the observed difference might be not only due to different inclusion criteria, but also due to variable prevalent biology of MDS in different ethnicities.
The other surprising finding was that despite significant differences in response and survival due to substantial number of patients in the analysis, the magnitude of difference was very modest almost for all of the mutations. The first studies identified significant impact of TET2 mutations on survival or response to therapy [24, 25], however after the accumulation of data in the other meta-analysis it was demonstrated that it is not a significant factor for response and survival [26]. The only exception found is the p53 mutation that has better primary response to therapy [11, 20], however it adversely affects survival compared to the other mutations, where despite lower response rates the survival was better. The study confirms the extremely negative impact of mutated p53 on prognosis that might not even be corrected by stem cell transplantation [27, 28]. Another finding is improved survival in the SF3B1 mutation cohort, however as with other mutations the magnitude of the difference was modest compared to the previous studies [29].
Despite the trend towards a lower frequency of responses in the presence of RUNX1 mutation, these data require further detailed testing, and it should be emphasized that no mutation associated solely with the lack of response to HMA therapy is currently known, which would allow discussion of the inadvisability of this type of treatment when clinically indicated [11].
Figure 4. Forest plot of survival and response to HMA with 95% confidence intervals.png
The observed confidence intervals of response to hypomethylating agents were comparable to the literature data of 40-50% [30, 31], with little variance due to mutational status, which raises the question, whether the mutational status is a good prognostic factor. On the other hand the clinical risk scales have a very good predictive power in terms of survival [29]. And the drawback of this study, as well as in every meta- analysis, was the absence of individual clinical prognostic features, thus the correction for clinical co-variables could not be made. With these co-variables the results of the study could be significantly different. This demonstrates the need for international cooperation and joining both the sequencing and clinical data from different institutions. This type of activity could have provided further understanding of MDS and the approaches to treat it.
The interesting group in this study was patients without mutations determined with sequencing. Interestingly, though they had the response rate around median, the survival of these patients was much more heterogenic then in the known mutations groups. It demonstrates that this is also a heterogenic group with variable prognosis. The underlining mechanisms are still to be determined. The most promising approach is further elucidation of microenvironment disturbances and changes in miRNA signaling that lead to MDS [32].
In conclusion, the study demonstrated, though significant, but moderate impact of mutations in patients with MDS on response to HMA. Further cooperative studies with sharing the clinical and sequencing data are required to understand MDS pathophysiology and approaches to treatment.

Acknowledgements

This work was supported by Russian Science Foundation, grant № 17-75-20145. Authors confirm the absence of any conflicts of interests.

References

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Introduction

Materials and methods

Data collection

Statistical analysis

Results

Frequency of mutations in the studied population

Response to HMA and overall survival associated with presence of specific mutations

Discussion

Acknowledgements

This work was supported by Russian Science Foundation, grant № 17-75-20145. Authors confirm the absence of any conflicts of interests.

References

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У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р<0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций. <h2 style="text-align: justify;">Ключевые слова</h2> Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты. 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Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(208) "Николай Ю. Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев
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Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р<0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций.

Ключевые слова

Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты.

Myelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р<0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations.

Keywords

Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis.

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In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р<0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations. <h2 style="text-align: justify;">Keywords</h2> Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2357) "

Keywords

Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis.

Keywords

Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis.

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Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(208) "Николай Ю. Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, 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" } ["DISPLAY_VALUE"]=> string(208) "Николай Ю. Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, 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) "20132" ["VALUE"]=> array(2) { ["TEXT"]=> string(3996) " Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р<0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций. <h2 style="text-align: justify;">Ключевые слова</h2> Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3926) "

Ключевые слова

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 allelles by means of intensive application of immunogenetic sequencing methods, including monoallelic Sanger-sequencing method, or, more recently, next-generation sequencing (Fig. 1). In June 2017, 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 17331 different HLA alleles, of which 12631 were HLA class I, and 4700 were found for the HLA class II alleles [1-3].

62-66 Fig. 1. A diagram showing increased numbers of HLA.png

The registration and name of new HLA alleles is carried out by the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System. The Committee developed a number of requirements ruling identification of the new HLA alleles (http://www.ebi.ac.uk/ipd/imgt/hla/subs/). In particular, the methods used to confirm new alleles should provide for separate sequencing of the alleles in the gene of interest. When performing HLA studies, appropriate primers should be used to determine the nucleotide sequence in forward and reverse directions. At the present time, sequencing of exons 2 and 3 is an obligatory requirement for identification of new HLA class I gene alleles. To verify any new alleles of HLA class II genes, one should perform the exon 2 sequencing.

The aim of this study was to evaluate the advantages of using monoallelic Sanger sequencing approach as a necessary step of identifying new HLA alleles.

Materials and methods

The test samples were obtained from potential donors of Bone Marrow Donor Registry of the I. P. Pavlov State Medical University in St. Petersburg and from a patient with acute myeloblastic leukemia who underwent HLA testing for subsequent allogeneic hematopoietic stem cell transplantation. Genomic DNA was isolated from peripheral blood leukocytes by a proteinase method using columns with a silica gel membrane and a kit PROTRANS DNA BOX reagents (Protrans, Germany). The target DNA concentration was 30 ng/ μL. Quantity and quality estimation of the isolated DNA was performed with Thermo Scientific NanoDrop 2000 Spectrophotometer. The quality of isolated DNA was estimated as an optical density ratio at of 260/280 nm wavelength, with reference range of 1.6-1.8.

Immunogenetic studies were done using the method of monoallelic Sanger sequencing. Initial and control studies were performed for each sample. To perform a control typing, the DNA was isolated from the newly collected biomaterial. The Protrans reagent kits (Germany) were used as follows: PROTRANS S4 HLA-A * Cyclerstrips, PROTRANS S4 HLA-B * Cyclerstrips, PROTRANS S4 HLA-C * Cyclerstrips, PROTRANS S4 HLA-DRB1 * Cyclerstrip, PROTRANS S3 HLADQB1 * Cyclerstrips. To identify HLA class I alleles (HLA-A, HLA-B, HLA-C), we sequenced exons 2-3; for class II HLA alleles (HLA-DRB1, HLA-DQB1) we sequenced exon 2.

Capillary electrophoresis was performed using Applied Biosystems 3500xl genetic analyzer (USA). To specify nucleotide sequences of the target alleles, the rough laboratory data were evaluated with Sequens Pilot software, version 4.1.2 (JSI Medical Systems, Germany).

Results

The method of monoallelic Sanger sequencing is routinely applied at the tissue typing laboratory of St. Petersburg State Medical University I. P. Pavlov since 2010. A special feature of this method is carrying out allele-specific PCR at the initial stage, which usually leads to separate amplification of the analyzed gene alleles. After separate amplification, each allele may be subject to isolated sequencing. The allele-specific sequencing allows of avoiding the socalled cis-trans ambiguities which occur when interpreting HLA typing results. About 90% of people are known to be heterozygous for each HLA gene, thus causing cis-trans ambiguities precluding the exact HLA genotyping after locus-specific sequencing [4].

Using an allele-specific sequencing approach, the novel alleles of HLA-B, HLA-DRB1, HLA-DQB1 genes have been identified in three potential bone marrow donors from the Bone Marrow Registry at the St. Petersburg State I.P. Pavlov Medical University, and in one patient from the R. Gorbacheva Memorial Research Institute for Children Oncology, Hematology and Transplantation. Later on, this patient underwent unrelated bone marrow transplantation [5-7].

HLA-B allele (B*44:02:45). A new HLA-B allele was detected in a potential bone marrow female donor (Caucasoid, living in St. Petersburg). As based on immunogenetic studies, the following HLA phenotype was determined: HLA-A*02:01:01G, *30:01:01G, HLA-B*13:02, *44new, HLA-C*05:01:01G, *06:02:01G, HLA-DRB1*04:02:01, *10:01:01G, HLA-DQB1*03:02:01,*05:01:01G. According to the version 3.26.0 of the IPD-IMGT/HLA database, we have revealed that the nucleotide sequence of exon 2 in the new HLA-B *44 allele differs from the most close homologue HLA-B*44:02:01:01 at position 243 (guanine substituted for thymine). As shown in Fig. 2, the nucleotide sequence of codon 81 GCG is changed to GCT. The substitution is synonymous since it does not lead to an amino acid change (alanine). The nucleotide sequence of the new HLA-B*44 allele was submitted to the GenBank database being available under the accession number KY039061 (http://www.ncbi.nlm.nih.gov/Genbank/). The name of new HLA-B*44 allele has been officially assigned as HLA-B*44:02:45 by the WHO Nomenclature Committee for Factors of the HLA System [3].

New alleles of HLA class II genes

HLA-DQB1 allele (DQB1*02:85). A new HLA-DQB1 allele was identified in a potential bone marrow donor (female, Caucasoid, from Leningrad Region). Immunogenetic studies showed following results: HLA-A*01:01:01G, *24:02:01G, HLA-B*08:01:01G, *39:01:01G, HLA-C*07:01:01G, *07:02:01G,HLA-DRB1*03:01: 01G, *04:04:01, HLA-DQB1*02new, *03:02. According to the version 3.26.0 of the IPD-IMGT/HLA database, the exon 2 sequence of the new HLA-DQB1*02 allele differs from the most close homologue HLA-DQB1*02:01:01 at the position 141 (cytosine replaced by adenine). As seen from Fig. 3, codon 47 is changed from TTC to TTA, thus causing an amino acid coding change (phenylalanine to leucine). Nucleotide sequence of the new HLA-DQB1*02 allele is available under the accession number KY014073 in the GenBank database. The new HLA-DQB1*02 allele has been officially assigned as HLA-DQB1*02:85 by WHO Nomenclature Committee for Factors of the HLA System [3].

HLA-DQB1 allele (DQB1*06:210). Another new HLADQB1 allele was detected in a patient with acute myeloblastic leukemia (female, Caucasoid, from Sverdlovsk Region). High-resolution HLA typing was performed to select an HLA compatible donor for allo-HSCT.

The following HLA phenotype was determined: HLA-A*03:01,*23:01/17/69, HLA-B*44:03, *50:01, HLA-C*04:01/09N/30/82,*06:02/83, HLA-DRB1*07:01/34, *13:01/117/190, HLA-DQB1*02:02,*06new. According to the version 3.26.0 of the IPD-IMGT/HLA database, the nucleotide sequence of exon 2 of the new HLA-DQB1*06 allele differs from the nearest homologue HLA-DQB1*06:03:01 at position 112 (thymine instead of guanine). The sequence of nucleotides in the codon 38 GCG is changed to TCG, thus leading to the amino acid replacement at position 38 (alanine replaced by serine, see Fig. 4). The nucleotide sequence of the new HLA-DQB1*06 allele is available under the accession number KX988007 in the GenBank database. The new HLA-DQB1*06 allele has been officially assigned as HLA-DQB1*06:210 by WHO Nomenclature Committee for Factors of the HLA System [3].

HLA-DRB1 allele (DRB1*01:01:30). A new HLA-DRB1 allele was detected in a potential bone marrow donor (male, Caucasoid, from Lipetsk). The HLA phenotype showed following distribution: HLA-A*01:01, *24:02, HLAB* 07:02/61/161N,*57:01, HLA-C*06:02/83, *07:02/50/349, HLA-DRB1*01:01new, *17:01/34, HLA-DQB1*03:03, *05:01. According to the version 3.26.0 of the IPD-IMGT/HLA database, the nucleotide sequence of the exon 2 of the new HLA-DRB1*01 allele differs from the nearest homologue HLA-DRB1*01:01:01 in position 279 (thymine is determined instead of guanine), for details see Fig. 5.

62-66 Figure 2. Comparison of sequence exon 2 alleles HLA-B.png

Fig. 4. Comparison of sequence exon 2 alleles HLA-DQB1.png

Fig. 5. Comparison of sequence exon 2 alleles HLA-DRB1.png

The sequence of nucleotides in codon 93 CGG is changed to CGT. The substitution is synonymous since a change in the amino acid (arginine) does not occur. The nucleotide sequence of the new HLA-DRB1*01 allele is available under the accession number KY026176 in the GenBank database. The new HLA-DRB1*01 allele has been officially assigned as HLA-DRB1*01:01:30 by the WHO Nomenclature Committee for Factors of the HLA System [3].

Conclusion

The results of our work are in accordance with previously published data [4, 8], which demonstrate the advantage of monoallelic Sanger sequencing which provide opportunity of the separate sequencing for the initially studied gene alleles, that allowing to resolve the ambiguities when interpreting HLA typing results. Thus, we may fulfill an important requirement of the WHO Nomenclature Committee for Factors of the HLA System which regulates the new HLA allele identification procedure.

Conflict of interest

The authors have declared no conflicting interests.

References

1. Robinson J, Halliwell JA, Hayhurst JH, Flicek P, Parham P, Marsh SGE. The 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. Biderman BV, Yakutik IA, Khamaganova EG, Sudarikov AB, Kuzmina LA, Savchenko VG. A new allele of Fig. 5. Comparison of sequence exon 2 alleles HLA-DRB1*01:01:01 and HLA-DRB1*01:01:30. The picture is created by means of the IPD-IMGT/HLA Database [1] HLA-C*12:138, detected in a patient with chronic myeloid leukemia in the process of searching for an unrelated donor for the transplantation of allogeneic hematopoietic stem cells. Gematologia i Transfusiologiya. 2015; 60(2):4–5 (InRussian).

5. Kuzmich E, Nasredinova A, Alyanskiy A, Afanasyev B. Identification of a new HLA-DQB1*06 allele, HLADQB1*06:210, by monoallelic Sanger sequencing. HLA. 2017; 90:132–133.

6. Kuzmich E, Makarenko O, Alyanskiy A, Afanasyev B. Detection of a new HLA-B*44 allele, HLA-B*44:02:45, by monoallelic Sanger sequencing. HLA. 2017; 90:124.

7. Kuzmich E, Tyapushkina S, Alyanskiy A, Afanasyev B. Identification of the novel HLA-DQB1*02:85 and HLADRB1*01:01:30 alleles in Russian individuals. HLA.2017; 90:135–136.

8. Loginova MA, Paramonov IV, Chalzov KV, Moore UV. The genetic characteristics of Novosibirsk donors of hematopoietic stem cells. Klinicheskaya Laboratornaya Diagnostika. 2016; 61(7):422–428 (In Russian).

" ["~DETAIL_TEXT"]=> string(14293) "

Introduction

62-66 Fig. 1. A diagram showing increased numbers of HLA.png

The aim of this study was to evaluate the advantages of using monoallelic Sanger sequencing approach as a necessary step of identifying new HLA alleles.

Materials and methods

Results

New alleles of HLA class II genes

62-66 Figure 2. Comparison of sequence exon 2 alleles HLA-B.png

Fig. 4. Comparison of sequence exon 2 alleles HLA-DQB1.png

Fig. 5. Comparison of sequence exon 2 alleles HLA-DRB1.png

Conclusion

Conflict of interest

The authors have declared no conflicting interests.

References

1. Robinson J, Halliwell JA, Hayhurst JH, Flicek P, Parham P, Marsh SGE. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Research. 2015; 43:D423-431.

3. Marsh SGE. Nomenclature for factors of the HLA system, update July 2017. Human Immunol. 2017; 78(11-12):758-761.

5. Kuzmich E, Nasredinova A, Alyanskiy A, Afanasyev B. Identification of a new HLA-DQB1*06 allele, HLADQB1*06:210, by monoallelic Sanger sequencing. HLA. 2017; 90:132–133.

6. Kuzmich E, Makarenko O, Alyanskiy A, Afanasyev B. Detection of a new HLA-B*44 allele, HLA-B*44:02:45, by monoallelic Sanger sequencing. HLA. 2017; 90:124.

7. Kuzmich E, Tyapushkina S, Alyanskiy A, Afanasyev B. Identification of the novel HLA-DQB1*02:85 and HLADRB1*01:01:30 alleles in Russian individuals. HLA.2017; 90:135–136.

С помощью метода моноаллельного секвенирования по Сэнгеру идентифицированы четыре новых HLA аллеля HLA-B*44:02:45, HLA-DQB1*02:85, HLADQB1*06:210, HLA-DRB1*01:01:30. Особенностью метода является выполнение на начальном этапе исследования аллель специфичной ПЦР, обеспечивающей последующую раздельную амплификацию аллелей анализируемого гена. Это, в свою очередь, позволяет выполнить изолированное секвенирование определенного аллеля и избежать неоднозначных результатов HLA типирования, наблюдающихся при выполнении локус-специфичного секвенирования. Изолированное секвенирование аллелей изучаемого гена является необходимым условием регистрации новых HLA аллелей Номенклатурным Комитетомпо факторам HLA системы Всемирной Организации Здравоохранения.

Ключевые слова

Главный комплекс совместимости, новые аллели HLA, моноаллельное секвенирование по Сэнгеру.

Four new HLA alleles were identified using the monoallelic Sanger sequencing method: HLA-B*44:02:45, HLADQB1*02:85, HLA-DQB1*06:210, HLA-DRB1*01:01:30. A distinctive feature of the method is to implement the initial allele-specific PCR products for subsequent separate amplification of the target gene alleles. This, in turn, allows for sequencing of each allele separately and avoiding ambiguous HLA typing results observed when performing locus-specific sequencing. The isolated sequencing of specific gene alleles is a sufficient requirement for the registration of new HLA alleles, as prescribed by the World Health Organization Nomenclature Committee for Factors of the HLA System.

Keywords

Major histocompatibility complex, novel HLA alleles, monoallelic Sanger sequencing.

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Keywords

Major histocompatibility complex, novel HLA alleles, monoallelic Sanger sequencing.

Keywords

Major histocompatibility complex, novel HLA alleles, monoallelic Sanger sequencing.

Ключевые слова

Главный комплекс совместимости, новые аллели HLA, моноаллельное секвенирование по Сэнгеру.

Ключевые слова

Главный комплекс совместимости, новые аллели HLA, моноаллельное секвенирование по Сэнгеру.

Introduction

Stroke is the third leading cause of death in Malaysia; it is also the major causal factor of severe and long-term functional disability in adults [1, 2]. There are two major types of stroke, namely ischemic stroke and hemorrhagic stroke. Ischemic stroke is characterized by thrombotic or embolic occlusion of cerebral artery, thereby restricts oxygen and nutrients supplies to an area of the brain. In contrary, hemorrhagic stroke is characterized by rupture of a blood vessel on or within the brain, subsequently causing severe bleeding into brain parenchyma. In Malaysia, most patients had ischemic stroke rather than hemorrhagic stroke [3].

In brain, neurons constantly demand for high glucose to perform cerebral functions [4]. Therefore, disrupted blood flow to the brain for as brief as 5 mins or less could be deadly to neurons. During ischemic stroke, interruption of blood flow attributed oxygen and glucose deprivation (OGD). Following OGD, the cellular metabolism switches from aerobic to anaerobic glycolysis for of adenosine triphosphate (ATP) production until existing pool of glucose is completely depleted [4]. Nevertheless, the efficiency of ATP production by anaerobic glycolysis is much lower compared to mitochondrial oxidative phosphorylation (OXPHOS) in which only 2 molecules of ATP for each molecule of glucose is produced compared to 34 ATP molecules produced under OXPHOS metabolism [5]. As a result, ATP consumption exceeds production and drives energy failure in the brain. In addition, anaerobic glycolysis also produces ion H+ and lactate, lowering the pH and causes rapid intracellular acidosis.

Following rapid ATP deficit, activity of ATP-dependent transport systems on the plasma membrane of neuron such as Na⁺/K⁺-ATPase, K⁺/Ca²⁺-ATPase and Ca²⁺-ATPase pumps also are affected [6]. Maintenance and restoration of ion gradients by these pumps are important to regulate neuron signaling processes such as postsynaptic and action potentials, as well as uptake and recycling of neurotransmitters [6]. Failure of the energy-dependent ion pump causes ionic imbalances which induce transient osmotic gradients in the brain, resulting in water influx, cell swelling, edema and ultimately initiates a cascade of pathophysiologic cellular and molecular mechanisms such as glutamate excitotoxicity, inflammation and free radical overload, leading to irreversible brain damage [7].

The cell death that occurs following ischemic stroke can be reduced if the occlusions are removed quickly and tissue reperfusion is restored. In stroke animal study, it had been demonstrated that damage could be limited if reperfusion occurred within three hours after the onset of stroke [8, 9]. Rapid restoration of blood flow to the infarcted brain tissue can be achieved by administration of thrombolytic agents which digest the clot. Existing pharmacological treatment for ischemic stroke including a combination of thrombolytic agent such as tissue plasminogen activator to break up blood clot, anti-platelet agents to prevent blood clots formation and/or statins to lower cholesterol levels in the blood [10]. Although current standard therapies allow restoration of blood supply or significant control against stroke symptoms, these treatments cannot completely restore the brain function because the central nervous system does not regenerate. A substantial portion of the lost brain functions can be regained by transferring the tasks to other neurons through stroke rehabilitation. Nonetheless, stroke rehabilitation is a long yet less efficient physical therapy. The limitation of these current stroke therapies has led to the demand for an alternative therapy to regenerate damaged brain tissue and restore total brain function [11].

Recently, stem cell therapy has emerged as a potential approach for treating neurodegenerative diseases and stroke. The transplanted cells may help to create new circuitry and express factors that protect existing cells. Neural stem cells (NSCs) are considered as the most optimal cell type for stem cell-mediated therapy of brain disorders. This is because they share the same tissue origin of the damaged brain cells and are originally meant to replenish the brain cells in vivo. By definition, NSCs are uncommitted cells that can self-renew extensively throughout lifetime or differentiate into different neuronal and glial subtypes in the brain [12]. In human brain, NSCs reside in two high-density cell division sites, the subventricular zone (SVZ) and subgranullar zone (SGZ) [13]. In the SGZ, NSCs reside along the lining of the dentate gyrus and hilus [14]. Hence, it is difficult to isolate SGZ-derived NSCs without damaging the surrounding brain tissue because they reside in the hippocampus interior. On the other hand, the SVZ is located at the lateral wall of the lateral ventricle [14]. The area is maintained in the adults as mitotically active area and NSC can be isolated endoscopically from this area for autologous transplantation [15]. Therefore, SVZ-derived NSCs provide the greater potential for clinical applications.

A number of publications have been described on isolation and expansion of human SVZ-derived biopsies [16-18]. The NSCs were expanded either through neurosphere [17, 18] or monolayer culture [16]. Nevertheless, no defined work has been performed to compare the efficiency of both neurosphere and monolayer culture for human NSC derived from a same SVZ biopsies. Furthermore, there is no previous study has been done in Hospital Universiti Sains Malaysia (Hospital USM) to excise human SVZ biopsy for NSC isolation. Therefore, in this study, we aimed a pilot study to isolate NSCs from the SVZ of patient with CVA or traumatic brain injury admitted to Hospital USM and developed a method for the isolation and expansion of NSCs for further stroke therapy study in Hospital USM. Besides, the method established in this study is specific to local genetic population profile, thus could potentially provide a more specific cell source for local NSC genetic and epigenetic study. According to Malaysian National Health and Morbidity Survey (NHMS), the prevalence of stroke among Malaysians increased sharply between 2006 and 2011 [2]. As a result, stroke causes an economic burden on health-care budgets and the whole nation economic development, reiterates the need for new therapies that can improve the effectiveness of stroke treatment for local population. Thus, the pilot clinical study described in this study is significantly useful for the researchers and clinicians in Hospital USM to establish future clinical application of stem cell-based therapy for stroke.

Materials and methods

Patient recruitment and tissue sampling

Patients admitted to Hospital USM with diagnosed cerebral vascular accident (CVA, i.e. ischemic or hemorrhagic stroke) or with moderate to severe head injury (Glascow Come Score (GCS) between 3 and 13) after computed tomography magnetic resonance image (CT-MRI) confirmation and necessitating brain resection were recruited. Patients with severe coagulation were excluded from the study. All participants provided their written informed consent to participate in this study. A total of nine (n=9) fresh surgical specimens sized <5mm³ were obtained from SVZ using the frameless stereotactic neuronavigation system by professional neurosurgeon team in Hospital USM. The tissue specimens were transported in a conical tube (BD Biosciences, USA) containing ice cold saline with 10% penicillin/streptomycin (GIBCO, USA) to the cell culture laboratory with minimal delay. The weight of the conical tube was measured before and after adding the biopsies to it. Then, the weight of the tissue specimen was obtained from subtraction of these two weights. All the procedure described here had been approved by the Human Research Ethic Committees, Universiti Sains Malaysia, FWA Reg. No.: 00007718; IRB Reg. No: 00004494.

Brain biopsy dissection and disaggregation

For the preparation of brain SVZ biopsy for stem cell isolation, the whole tissue was removed from the ice-cold conical tube onto a sterilized petri dish in a clean Biosafety Cabinet. The tissue specimen was rinsed with ice cold D-PBS without calcium and magnesium (Invitrogen, USA) to remove excess blood or connective tissue before dissected into small explants on ice using surgical blade. After microdissection, the tissue explants were digested using 0.05% Trypsin-EDTA (Invitrogen, USA) for 5 minutes at 37⁰C to further disaggregate the tissue. After 5 minutes, the enzymatic dissociation was inhibited by addition of equal amount of soybean trypsin inhibitor (Sigma, USA) with Deoxyribonuclease I (DNase I) (Sigma, USA). To achieve a single cell suspension, the cell suspension was subjected to sequential trituration using pipettes of decreasing diameter. Then, the cell suspension was filtered through a 40 μm cell strainer to remove cell debris. The cell suspension was spun at 1500 rpm for 5 minutes and the cell pellet was resuspended in 1ml of NSC serum-free media comprised of 1X Knockout D-MEM/F-12 (GIBCO, USA), 2 mM Glutamax I supplement (GIBCO, USA), 50X B27 supplement (GIBCO, USA), 20 ng/mL basic Fibroblast Growth Factor (bFGF) (GIBCO, USA) and 20 ng/mL Epidermal Growth Factor (EGF) (GIBCO, USA) and 2 mg/mL Heparin (STEMCELL Technologies, USA).

Coating cell culture flasks for human NSC isolation

Culture vessels were coated with either Poly-D-lysine (PDL)/laminin (Sigma, USA) or CELLstart^TM CTS^TM (GIBCO, USA) coating agent. To coat a T-25 flask with PDL/laminin, 3 mL of 10 μg/mL PDL was added and incubated for 2 hours at 37⁰C. Then, the PDL solution was removed completely and rinsed thoroughly twice with 3 mL of cell culture grade water because excess PDL can be toxic to the cells. Next, 3 mL of 10 μg/mL laminin solution was added and incubate at 37⁰C, in the dark, for 2 h. Prior to use, the flask was washed twice with 4 mL of DPBS without calcium and magnesium. On the other hand, to coat a T-25 flask with CELLstart^TM CTS^TM, 20 μL of CELLstart^TM CTS^TM was diluted in 2 mL of 1X D-PBS with calcium and magnesium and added into a T-25 flask. The flask was then incubated at 37⁰ C in a humidified chamber with 5% CO₂ for 1 h. Used CELLstart^TM CTS^TM was aspirated and the coated culture vessels were rinsed once with 3 mL of 1X D-PBS without calcium and magnesium prior to cell seeding.

Isolation of human Neural Stem Cells (NSCs)

The total number of viable cells after enzymatic dissociationwas determined by cell counting using CountessTM automatedcell counter. Briefly 10 μL of single cell suspension inNSC serum-free media was aspirated and diluted in 10 μL of 0.4% trypan blue solution. The cells were mixed completely and 10 μl of the cells was carefully filled into the Countess^® cell counting chamber slide. Non-viable cells appeared blue whilst viable cells remained opaque. In this work, only viable cells were included in calculation of the cell concentration. After cell counting, the cells were split into two portions and cultured using two different methods namely: neurosphere culture or adherent monolayer culture. For neurosphere culture, the cell suspension was added to non-coated T-25 flask, while for adherent monolayer culture, the cell suspension was added to pre-coated T-25 flask (as described in previous section). For both methods, the cells were seeded at a final density of 1.0x105 cells/cm² and incubated in a humidified incubator under 5% CO₂ at 37⁰ C for up to 4 weeks or until the monolayer cell got confluent or the free-floating spheres achieved within 150 μm in diameter. Thereafter, the cells were harvested and passaged.

Immunocytochemistry

The harvested cells were seeded onto CELLstart^TM CTS^TMcoated glass coverslips in a 24-well plate and incubated at 37⁰C in the standard CO₂ incubator until the monolayer cell get 70% confluent. Prior to ICC, the medium was discarded and the cell monolayer was rinsed with 500 μL of 1X D-PBS with calcium and magnesium. The cells were fixed, permeabilized and blocked. Then, the cells were probed with anti-nestin (NSC marker) (Pierce, MA1-110) and anti-TUBB3 (neuron marker) (Novus Biologicals, NB100-479) or anti-GFAP (glial marker) (Abcam, ab7260) primary antibodiesfor double staining. A second incubation was performed using anti-mouse IgG-Alexa Fluor^® 488 (Abcam, ab150105) and anti-rabbit IgG-Alexa Fluor^® 555-conjugated (Abcam, ab150074) secondary antibodies. The cells were counterstained with NucBlue^® (DAPI) (Invitrogen, USA) fixed cell stain and mounted on glass slides using ProLong^® Diamond Antifade Mountant (Molecular Probes, USA).

Results

Biopsy Weight

Biopsies were successfully obtained from SVZ of nine patients. The weight of biopsies ranged from 0.04 g to 0.12 g (Table 1).

52-61 Table 1. The weight of SVZ biopsies collected from eight.png

Primary Human NSC

Based on the result obtained, we summarized and divided the clinical samples into following three groups having three samples in each group. Group 1: NSC cultured on PDL/Laminin coated flask; Group 2: NSC cultured on CELLstart^TM CTS^TM coated flask; Group 3: NSC cultured on CELLstart^TM CTS^TM coated flask with optimized tissue sampling techniques.

Group 1: Patient 1, 2 and 3

In primary human NSC culture of Patient 1, the tissue biopsy obtained was initially digested and divided into two flasks: a PDL/Laminin coated T25 flask and an uncoated T25 flask. Theoretically, neural stem and progenitor cells should attach to the PDL/Laminin coated surface after 24 hours in vitro and grow into monolayer with phase bright sphere cells within 7-14 days of culture. On the other hand, in the uncoated flask, neural stem and progenitor cells should aggregate and grow into freely floating neurosphere of approximately 150 μm in diameter within 7-14 days in vitro. However, here, we did not observe any bright sphere cells attached to the PDL/Laminin coated layer or any neurosphere aggregated in uncoated flask. On the other hand, high densities of cell debris with spherical shape were found in the culture media after 24 hours in vitro. These results contradicted with our expectation, therefore, the cell suspension from both coated and uncoated flasks were harvested and then further divided into three respective coated and uncoated flasks to double confirm the observation. Yet, after 4 weeks of trial, neural stem and progenitor monolayer cells and neurosphere were still not detected in any of the flasks. Approaching the end stage of experiment, only several neuronal-like cells were found attached in one of the coated flask of Patient 1 (Fig. 1A). Similar results were obtained for the SVZ tissue biopsy obtained from Patient 3, in which, upon approaching the end stage of experiment, only several neuronal-like cells were found attached in one of the coated flask of Patient 3 (Fig. 1B and C). No monolayer cells or neurospheres were observed.

For Patient 2, interestingly, we observed a totally different cell growth pattern compared to Patient 1 and Patient 3. In this patient, monolayer of stem and progenitor cells were found grow on all PDL/Laminin coated flasks (Fig. 2A). The Fig. 1. Neuronal-like cells found in PDL/Laminin coated T-25 flasks of (A) Patient 1 and (B) (C) Patient 3 after 4 weeks in vitro (indicated by red arrows) monolayer cells proliferated slowly and became confluent after 4 weeks in vitro. For non-adherent culture, we observed only two neurospheres floated in the media (Fig. 2B). We also observed some cells outgrew from the edge of neurosphere, suggesting the clonal feature of the neurosphere which mimic the stem cell self-renewal characteristics. However, the outgrowth rate was not as rapid as compared to the monolayer cell culture method. After 4 weeks, the cells were harvested and passaged. Unfortunately, the cells were contaminated by bacterial growth after 2 days. Thus, not enough cells were harvested for subsequent characterization assays.'

Based on the result obtained for group 1 patients, it was proved that the pilot testing of human NSC culture method done in this study was successful in some extent. We also found that the adherent culture method produced better yield of stem and progenitor cells compared to non-adherent culture method. Therefore, adherent culture system was applied in all subsequent experiments. Furthermore, we modified the adherent coating agent in subsequent experiments to optimize the cell culture method.

52-61 Fig. 1. Neuronal-like cells found in PDL Laminin coated.png

52-61 Fig. 2. (A) Monolayer cell and (B) two neurospheres (indicated.png

Group 2: Patient 4, 5 and 6 (optimized adherent culture method)

For primary NSC culture of Patient 4, CELLstart^TM CTS^TMcoated T25 flask was used to culture cell suspension obtained from SVZ brain tissue. CELLstart^TM CTS^TM was used to replace PDL/laminin as coating agent due to several reasons. First, the incubation time for CELLstart^TM CTS^TM coating method was much shorter than PDL/laminin (1 hour vs 4 hours). This can help to reduce the waiting period after tissue biopsy was excised from patient’s brain. Second, CELLstart^TMCTS^TM coating solution was manufactured by GIBCO Invitrogen while PDL/laminin coating solution was self-prepared by researcher in our lab. Thus, the stability and accuracy of CELLstart^TM CTS^TM coating solution was better as compared to PDL/laminin coating solution. The result obtained proved our hypothesis. Neural stem and progenitor cells were found attached to the CELLstart^TM CTS^TM coated surface after 24 hours in vitro and grew into monolayer with phase bright sphere cells after several days (Fig. 3A). After 2 weeks, a confluent monolayer cell with neurospheres attached on the coated layer was observed as shown in Fig. 3B. These cells were harvested and passaged under similar adhesion substrate. We observed similar confluent monolayer cell with neurospheres attached on the coated layer after a week (Fig. 3C), proved that these cells possessed active proliferation property. Besides, when the neurospheres was harvested and replated, the neurosphere was found to spread and grew into monolayer (Fig. 3D). These cells were harvested and characterized using immunohistochemistry assay and showed significant expression of Nestin which is a specific marker of NSC (Fig. 4). Besides, the negative staining of GFAP (Fig. 4A) and TUBB3 (Fig. 4B) also further confirmed that these cells were not the glial cell or neuron cells from brain biopsy.

Fig 4. Immunofluorescence images of primary human NSC characterization. Monolayer cell from Patient 4 was positive.png

Fig 4. Immunofluorescence images of primary human NSC characterization. Monolayer cell from Patient 4 was positive 1.png

In the primary NSC culture of Patient 5, neural stem and progenitor cells were not found in the CELLstart^TM CTS^TM coated T-25 flask. On the other hand, abundant erythrocytes were detected in the culture media (Fig. 5A). After 2 weeks, several neuronal-like cells were attached on the coated layer (Fig. 5B). This was probably due to the error happened during tissue sampling as it was found that most of the tissue excised was blood and connective tissue with minimal visible neuronal tissue (Fig. 5C). The weight of tissue specimen was only 0.04g, the least among the rest (Table 1).

Fig. 5. Primary NSC culture from SVZ biopsy of Patient.png

Fig. 6. Primary NSC culture from SVZ biopsy of Patient 6..png

After collected data for group 2 patients, it was proved that the technique of tissue sampling and timing to process the tissue specimen without delay are crucial for successful isolation of NSC from human SVZ. We compiled and summarized data obtained and set out a clear sampling standard and applied it in all subsequent experiments.

Group 3: Patient 7, 8 and 9 (using optimized tissue sampling method)

Biopsy from patient 7, 8 and 9 were obtained successfully with high quality, weighted 0.10 to 0.12 g with no attached blood or connective tissue (Fig. 7A). The tissue specimens were also processed immediately after excision without delay. For all these samples, neuronal cells and neurosphere- like cells were successfully obtained (Fig. 7B-D) and were remained viable for up to 4 weeks. The cells were passaged, cryopreserved and kept for future study. This pilot study had been successfully done to set up a basic guideline for cell culture method and tissue sampling standard for future SVZ-derived NSC research in Hospital USM.

Fig. 7. Primary NSC culture from SVZ biopsy of Patient.png

Fig. 7. Primary NSC culture from SVZ biopsy of Patient (1).png

Discussion

SVZ harbors abundant NSCs for neurogenerative therapy. SVZ-derived NSCs are located within the lateral wall of the lateral ventricle and can be isolated endoscopically for autologous transplantation. NSCs are endogenous brain stem cells which function to replenish the brain cells in vivo [19]. Therefore, these cells have great potential to regenerate damaged brain tissue after ischemic stroke. Furthermore, NSCs also have a lower oncogenic potential and immunological rejection as compared to other stem cell types after transplantation [20], therefore, these cells are suitable as therapeutic agent for stroke regenerative treatment.

In this study, SVZ biopsy was obtained with the utilization of stereotactic biopsy needle under neuronavigation system. The advantage of stereotactic approach was the ability to obtain small sized specimen with minimal damage to the neighbouring tissue. This is particularly important to eliminate unnecessary side effects to the donor. Furthermore, proper specimen storage during transportation and minimal delay in specimen processing are crucial to establish primary culture. Any delay or mistakes during the transportation procedure could propagate damage on the excised tissue and affect the efficiency of stem cell isolation. During processing of specimen, enzymatic dissociation using trypsin was performed on finely minced tissues to provide maximum cell recovery and viability. DNase I was also used together with soybean trypsin inhibitor to eliminate membrane-bound DNA and reduce the viscosity.

Under adherent condition, NSCs formed a monolayer cell on adhesion substrate while in the absence of adhesive coating medium, NSCs formed cluster of floating spherical cells known as neurosphere. Nonetheless, overgrown monolayer may also lead to the growth of neurosphere that attached on the adhered cells. Although NSC had limitless potential to proliferate into neurosphere for several passages, the neurospheres obtained from two patients failed to propagate beyond tertiary spheres as compared to previous studies [18, 21]. On the other hand, in this study, monolayer culture managed to expand NSCs beyond passage 3. The ICC results also further validated the stemness of monolayer cell obtained from patients. Thus, this study proposed that neurosphere culture may not be suitable for human SVZ biopsies due to low cell number generated. The neuronal-like cells obtained from other patients suggested that the biopsies were derived from non-neurogenic niches such as blood, connective tissue and perhaps the white matter. Hence, further biopsy required proper target of the NSC niche. It is pivotal to collect the biopsy from the lateral ventricle of the SVZ which may generate sufficient proliferating NSC for several passages.

Here, we tried to analyse the preliminary demographic profile of all the recruited patients with the yield of NSC obtained. Notably, no significant association was able to establish from the patient’s reports due the limited sample size and high variability across samples. Therefore, it is imperative to specify recruitment criteria and increase sample size.

Conclusion

NSC can be isolated from the SVZ of patients with CVA or traumatic brain injury using stereotactic approach. NSC propagated better in adherent culture coated with CELLstart^TM CTS^TM as compared to non-adherent culture. Precise SVZ tissue sampling with minimal variability and processing time is required to obtain significant successfully NSC isolation. Further studies with bigger sample sizes are required for a complete demographic profile. Nonetheless, this pilot study successfully set a basic guideline for cell culture method and tissue sampling standard for future SVZ-derived NSC research in Hospital USM. Data obtained from this study could be a stepping stone for the establishment of clinical application of SVZ-derived NSC for clinical stroke therapy in Hospital USM.

Acknowledgements

This study was funded by USM Research University Individual (RUI) Grant (Grant no: 1001/PPSK/812140). Kang In Nee’s studentship is sponsored by MyBrain15, Ministry of Higher Education Malaysia.

No conflicts of interest are reported.

Author contribution statement

T.S.C. and S.S developed the concepts and designed the experiments. A.R.I.G. performed brain surgery and acquired clinical samples. K.I.N acquired research data. T.S.C. and K.I.N analysed and interpreted the data. T.S.C. and K.I.N wrote the manuscript. T.S.C and K.I.N proofread and gave final approval of the version to be published.

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