ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 2, Number 2(6)
03/01/2011
Volume 2, Number 2(6)
Editor-in-Chief
Afanasyev B. V. (St. Petersburg, Russia)
Co-Editors-in-Chief
Wagemaker G. (Rotterdam, Netherlands)
Zander A. R. (Hamburg, Germany)
Deputy Editor
Chukhlovin A. B. (St. Petersburg, Russia)
Fehse B. (Hamburg, Germany)
Novik A. А. (Moscow, Russia)
Managing Editor
Claudia Koltzenburg (Hamburg, Germany)
Editorial Board
Aleynikova O. (Minsk, Belarus)
Alyansky A. (St. Petersburg, Russia)
Anagnostou A. (Boston, USA)
Andreeff M. (Houston, USA)
Bacher U. (Hamburg, Germany)
Baуkov V. (St. Petersburg, Russia)
Baranov V. S. (St. Petersburg, Russia)
Barkhatov I. (St. Petersburg, Russia)
Baum C. (Hannover, Germany)
Bilko N. (Kiev, Ukraine)
Borset M. (Trondheim, Norway)
Buechner Th. (Muenster, Germany)
Bykov V. (St. Petersburg, Russia)
Dini G. (Genoa, Italy)
Drize N. (Moscow, Russia)
Egeland T. (Oslo, Norway)
Elstner E. (Berlin, Germany)
Emanuel V. (St. Petersburg, Russia)
Everaus H. (Tartu, Estonia)
Ferrara J. (Ann Arbor, USA)
Fibbe W. (Leiden, Netherlands)
Galibin O. (St. Petersburg, Russia)
Ganser A. (Hannover, Germany)
Granov D. (St. Petersburg, Russia)
Ivanov R. (Moscow, Russia)
Klimko N. (St. Petersburg, Russia)
Kolb H.-J. (Muenchen, Germany)
Konopleva M. (Houston, USA)
Koza V. (Pilsen, Czech Republic)
Kroeger N. (Hamburg, Germany)
Malikov A. (St. Petersburg, Russia)
Mikhailova N. (St. Petersburg, Russia)
Mentkevich G. (Moscow, Russia)
Nagler A. (Tel Hashomer, Israel)
Nemkov A. (St. Petersburg, Russia)
Neth R. (Hamburg, Germany)
Nevorotin A.J. (St. Petersburg, Russia)
Ostertag W. (Hamburg, Germany)
Palutke M. (Detroit, USA)
Roumiantsev A. G. (Moscow, Russia)
Savchenko V. G. (Moscow, Russia)
Smirnov A. V. (St. Petersburg, Russia)
Stamm C. (Berlin, Germany)
Tetz V. (St. Petersburg, Russia)
To B. (Adelaide, Australia)
Totolian A. A. (St. Petersburg, Russia)
Uss A.L. (Minsk, Belarus)
Vilesov A. (St. Petersburg, Russia)
Westenfelder Ch. (Salt Lake City, USA)
Wisloff F. (Oslo, Norway)
Zubarovskaya L. (St. Petersburg, Russia)
Zvartau E. (St. Petersburg, Russia)
In this Issue

Milestone

Precursor cells in the hematopoietic stromal microenvironment

Joseph L. Chertkov, Olga A. Gurevitch, Gennadiy A. Udalov, Irina N. Shipounova, Nina J. Drize

Forum

Reviews

Articles

Three strategies of autologous hematopoietic stem cell transplantation in multiple sclerosis

Andrei A. Novik1, Aleksey N. Kuznetsov1, Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatyana I. Ionova2, Kira A. Kurbatova2

The feasibility of high dose chemotherapy with autologous stem cell transplantation for multiple sclerosis

Evgeny P. Evdoshenko1, Lyudmila S. Zubarovskaya2, Leonid G. Zaslavsky1, Alexander A. Skoromets3, Sergey A. Alexeev4, Julia A. Stankevich4, Natalia A. Totolyan3, Boris V. Afanasyev2

Patient-reported outcomes in multiple sclerosis patients undergoing autologous stem cell transplantation

Tatyana I. Ionova1, Denis A. Fedorenko2, Nikita E. Mochkin2, Kira A. Kurbatova1, Andrey A. Novik2

The generation and properties of human M2-like macrophages: potential candidates for CNS repair?

Elena R. Chernykh, Ekaterina Ya. Shevela, Ludmila V. Sakhno, Marina A. Tikhonova, Yaroslav L. Petrovsky, Alexander A. Ostanin

Other topics

Therapy of acute graft-versus-host disease

Malte von Bonin, Martin Wermke, Uwe Platzbecker, Jörgen Radke, Nona Shayegi, Susanne Gretzinger, Konrad Heuchel, Kristina Hölig, Marc Schmitz, Gerhard Ehninger, Johannes Schetelig, Martin Bornhäuser

Milestone

Precursor cells in the hematopoietic stromal microenvironment

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Joseph L. Chertkov, Olga A. Gurevitch, Gennadiy A. Udalov, Irina N. Shipounova, Nina J. Drize

National Research Center for Hematology, Moscow, Russia

The manuscript summarizes the works of Prof. Joseph Chertkov that are dedicated to precursor cells in the hematopoietic stromal microenvironment. Unique functional analysis was used in these investigations. The properties of stem cells in the hematopoietic microenvironment such as self-renewal capacity and the ability to differentiate into all stromal lineages are described. The hierarchical structure of stromal precursor cells compartment is proposed. Some elements of the regulatory pathways of stromal precursor cells are described. This compilation reflects the importance of Prof. Chertkov’s contribution to the investigation of stromal precursor cells and hematopoiesis.

Forum

Reference Management meets Web 2.0

Martin Fenner, MD

Carl-Neuberg-Str. 1, Hannover Medical School, 30625 Hannover, Germany

Reference management software has been used by researchers for more than 20 years to find, store, and organize references, and to write scholarly papers. Recently developed collaborative web-based tools have resulted in a number of interesting new features, and in a number of new reference managers. These developments are changing which reference managers we use, and how we use them.

Keywords

RTEmagicC_RTEmagicC_Fenner_Keywords.gif

reference management, Web 2.0, citation


Reviews

Hematopoietic stem cell transplantation for severe autoimmune diseases: Progress and perspectives

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Alberto M. Marmont

II Division of Hematology and Stem Cell Transplantation, Center Azienda Ospedaliera-Universitaria S. Martino, Genoa, Italy

Two different sets of investigation are at the origin of hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (SADs). The experimental evidence consisted in the transfer/cure of animal SADs as murine lupus by means of allogeneic but also, almost paradoxically, autologous HSCT.  The clinical arm comes from serendipitous reports of patients allotransplanted for coincidental diseases, and ultimately cured of both conditions. Important multicentric prospective trials are ongoing to compare ASCT to the best available non-transplant therapies, but it may be argued that in the end both approaches will be integrated for single patients, and that new agents will possibly alter present strategies. Allogeneic STC is eliciting great expectations, but the burden of higher mortality and morbidity as a result of GVHD in the first place must be considered, even when making recourse to reduced conditioning regimens (RIC).

Keywords

autoimmune diseases, hematopoietic stem cell transplantation

Reviews

On the evolution of high-dose immunosuppressive therapy with autologous stem cell transplantation in multiple sclerosis

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Athanasios Fassas

Department of Hematology and Bone Marrow Transplantation Unit, Cell and Gene Therapy Unit, George Papanicolaou Hospital, Thessaloniki, Greece

High-dose immunosuppressive therapy with hemopoietic stem cell transplantation (HSCT) was already introduced into the management of multiple sclerosis (MS) in 1995. HSCT has been shown to be a most powerful immunosuppressive and anti-inflammatory treatment. Since 2000, all communications have consistently reported a dramatic, almost 100%, reduction in, or disappearance of, disease activity (inflammation) on magnetic resonance imaging (MRI), which is retained over time and has not been observed as an outcome of any other MS treatment. Despite the very interesting outcomes of HSCT in treatment of MS, it is only in comparative trials that its superiority over other therapies can be demonstrated. Therefore, it is absolutely necessary to complete the running randomized studies comparing HSCT with mitoxantrone (ASTIMS) or other standard therapies. Unless such trials yield their final results, HSCT will never be approved as an established therapy for MS patients who may so miss the opportunity of receiving an active, powerful immunosuppressive and immunomodulating treatment having a long-term beneficial impact on the course of the disease.

Reviews

Theoretical and practical issues of autologous versus allogeneic stem cell transplantation in multiple sclerosis

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Alois Gratwohl

Department of Hematology, University of Basel, Switzerland

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) have some common and some clearly distinct goals. All current available information suggests that autologous HSCT should remain the standard approach to clinical HSCT for patients with severe autoimmune disorders, including multiple sclerosis. Allogeneic HSCT should be considered in rare patients with specific features that they are likely to benefit more from an allogeneic HSCT, e.g. young patients with no co-morbidities and hematological autoimmune cytopenias.

Articles

Three strategies of autologous hematopoietic stem cell transplantation in multiple sclerosis

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Andrei A. Novik1, Aleksey N. Kuznetsov1, Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatyana I. Ionova2, Kira A. Kurbatova2

1Pirogov National Medical Surgical Center, Moscow, Russia; 2Multinational Center for Quality of Life Research, Saint Petersburg, Russia


Correspondence
Professor Tatyana I. Ionova, Multinational Center for Quality of Life Research, 1 Artilleriiskaya str., 191014 St. Petersburg, Russia
E-mail: tion16@spam is badmail.ru

High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (ASCT) is a promising approach to the treatment of multiple sclerosis (MS) patients. The data obtained points to the feasibility of early, conventional, and salvage HDIT +ASCT in MS patients. Further studies should be done to investigate clinical and patient-reported outcomes in MS patients receiving early, conventional, and salvage transplantation to better define treatment success. The concept of HDIT +ASCT in MS opens a new window of opportunity for treatment of this patient population.

Keywords

multiple sclerosis, autologous stem cell transplantation, long-term clinical outcomes, early ASCT, conventional ASCT, salvage ASCT

Articles

The feasibility of high dose chemotherapy with autologous stem cell transplantation for multiple sclerosis

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Evgeny P. Evdoshenko1, Lyudmila S. Zubarovskaya2, Leonid G. Zaslavsky1, Alexander A. Skoromets3, Sergey A. Alexeev4, Julia A. Stankevich4, Natalia A. Totolyan3, Boris V. Afanasyev2

1Leningrad Region Center for Multiple Sclerosis, Leningrad Region Clinical Hospital/ Chair of Neurology, Department of Neurology, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia; 2Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia; 3Chair of Neurology, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia; 4BMT Unit for adults, Memorial R.M. Gorbacheva Institute of Children Hematology and Transplantation, St. Petersburg Pavlov State Medical University, St. Petersburg, Russia

The results of observing 23 patients with multiple sclerosis who received autologous hematopoietic stem cell transplantation are shown in this article. The risks of an auto-HSCT and its advantages compared with other therapy methods, and also an optimal choice for the therapy predictors are discussed. The results show progress of disease in most cases after 12-18 months.

Keywords

autologous hematopoietic stem cell transplantation (auto-HSCT), multiple sclerosis

Articles

Patient-reported outcomes in multiple sclerosis patients undergoing autologous stem cell transplantation

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Tatyana I. Ionova1, Denis A. Fedorenko2, Nikita E. Mochkin2, Kira A. Kurbatova1, Andrey A. Novik2

1Multinational Center for Quality of Life Research, St. Petersburg, Russia; 2Department of Hematology and Cellular Therapy, Pirogov National Medical Surgical Center, Moscow, Russia


Correspondence
Tatyana I. Ionova, 195009, Finski per., 9, mailbox 57, St. Petersburg, Russia
Phone/Fax: +7 (812) 436-61-12, E-mail: qlife@spam is badrambler.ru

Physical, psychological, and social function in MS patients is significantly deteriorated. Quality of life profile of the patients is characterized by compression and deformation. The majority of the patients exhibit either severe or critical QoL impairment. MS patients experience a wide range of disease-related symptoms; the most frequent symptoms are fatigue, toddling, heat sensitivity, psychological problems (anxiety and sadness), and numbness/tingling are present in more than 70% of patients. About half of all patients report these symptoms at the moderate-to-severe level. ASCT in MS patients improves their physical, psychological, and social function. The most definite improvement of quality of life takes place within a year of transplantation. After ASCT the number of patients with no QoL impairment increases and the number of patients with critical QoL impairment decreases. Quality of life treatment response was achieved in the vast majority of MS patients after ASCT. ASCT is associated with decline of symptom prevalence and severity in MS patients.

Articles

The generation and properties of human M2-like macrophages: potential candidates for CNS repair?

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Elena R. Chernykh, Ekaterina Ya. Shevela, Ludmila V. Sakhno, Marina A. Tikhonova, Yaroslav L. Petrovsky, Alexander A. Ostanin

Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology of Russian Academy of Medical Sciences, Siberian Branch, Novosibirsk, Russia


Correspondence
Elena Chernykh, Laboratory of Cellular Immunotherapy, Institute of Clinical Immunology RAMS SB, Yadrintsevskaya str., 14, Novosibirsk, 630099, Russia
Phone: +7(383)2360329; Fax: +7(383)2227028; E-mail: ct_lab@spam is badmail.ru

Regulation of the immune response seems to be a promising strategy for a successful central nervous system (CNS) repair, and macrophages are considered to be prospective candidates for cell therapy. Using low serum conditions we generated human anti-inflammatory M2-like macrophages from peripheral blood monocytes and compared these cells (termed Mφ3) with “standard” pro-inflammatory Mφ1 and anti-inflammatory Mφ2, generated in the presence of GM-CSF and M-CSF. We focused primarily on the differences in T-cell stimulatory activity and production of various cytokines, chemokines, and growth factors. Low serum conditions had no negative impact on macrophage yield, the largest of which was for Mφ3. We showed that Mφ3 more closely resembled Mφ2 than Mφ1. Mφ2 and particularly Mφ3, but not Mφ1 expressed relatively low levels of CD86 and failed to stimulate T-cell proliferation. In contrast to pro-inflammatory Mφ1, unstimulated Mφ3 produced significantly lower levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-18, IL-12) and Th1/Th2-cytokines (IFN-γ, IL-2, IL-4) coupled with a higher IL-10 level. Moreover, concentrations of IL-1β and pro-inflammatory chemokines IL-8 and MCP-1 in Mφ-3 supernatants were lower not only when compared to Mφ1, but also to Mφ2 cultures. Like Mφ1 and Mφ2, Mφ3 was capable of producing neurotrophic- (BDNF, IGF-1), angiogenic- (VEGF), and other growth factors (EPO, G-CSF, FGF-basic, EGF) with neuroprotective and regenerative activity. In fact, IGF-1 production by Mφ-3 exceeds secretion of this factor by Mφ-1 and Mφ-2 by more than 25 fold. Thus, generated Mφ-3 represented M2-like macrophages with high regenerative potential.

Other topics

Systemic treatment of chronic GVHD

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Michael Schleuning

Zentrum für Blutstammzell- und Knochenmarktransplantation, Wiesbaden, Germany

Severe chronic graft versus host disease (GVHD) is the main factor for late morbidity and mortality in long-term survivors after allogeneic hematopoietic cell transplantation. The only established treatment of chronic graft versus host disease is the use of high dose corticosteroids. However, multiple different treatment approaches have been evaluated mostly in small phase 2 studies. These included calcineurin inhibitors for blocking T-cell activation, classical cytotoxic drugs, like methotrexate or azathioprine, as well as immunomodulatory substances like cytokine inhibitors or thalidomide. More recently novel treatment approaches have been evaluated. These include the use of B-cell antibodies and the tyrosine kinase inhibitor imatinib. Furthermore treatment options beyond mere immunosuppression that aim to induce tolerance are currently under investigation. These include extra-corporal photopheresis and treatment with inhibitors of the mammalian target of rapamycin. This review will discuss these different treatment approaches.

Keywords

chronic GVHD, calcineurin inhibitors, mTOR, extracorporal photopheresis, immunomodulatory drugs, steroids, methotrexate

Other topics

Graft-versus-Leukemia (GVL) activity in childhood leukemias

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Claudia Rossig

University Children's Hospital Muenster, Department of Pediatric Hematology and Oncology, Muenster, Germany

Allogeneic hematopoietic stem cell transplantation (HSCT) today contributes significantly to the cure of children with high-risk leukemias. The contribution of cellular graft-versus-leukemia (GVL) reactions to the anti-leukemic effects of allogeneic transplantation in pediatric leukemias has not been clarified in detail. Evidence is mainly based on indirect associations of clinical signs of alloreactivity with maintenance of full donor chimerism and relapse-free survival. Therapeutic interventions aimed at deliberately enhancing alloreactive donor cells via early reduction of immunosuppression or administration of donor lymphocytes are limited by the occurrence of graft-versus-host-disease (GVHD). Therefore, an important goal in advancing the use of allogeneic HSCT as treatment for childhood leukemias is the development of therapeutic strategies that induce or augment GVL effects while avoiding GVHD. One potential strategy relies on genetic modification of the receptor specificity of T cells or NK cells to recognize leukemia-associated antigens. Current efforts further focus on an optimal in vivo functionality of therapeutic T cells, including homing to the leukemia microenvironment, persistence, and capacity for specific reactivation.

Keywords

leukemia, pediatric oncology, T cells, immunotherapy, adoptive T cell transfer

Other topics

Mechanisms of graft-versus-leukemia effects after allogeneic stem cell transplantation (videolection)

Hans-Jochem Kolb

Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Großhadern, Germany


Correspondence
Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Großhadern, Marchioninistrasse 15, 81337 Munich, Germany
E-mail: Hans.Kolb@spam is badmed.uni-muenchen.de

Videolection

The lecture begins by describing the historical features of hematopoietic stem cell transplantation (HSCT), followed by the first clinical experiences with T cell-depleted allografts. A concept of adoptive immune therapy is proposed for chimeric organisms after T-cell depleted grafting, aiming for an increased graft-versus-leukemia (GvL) effect.

The efficiency of donor lymphocyte transfusions (DLT) was extensively tested, being more expressed  in chronic myeloid leukemia (CML). The intensity of graft-versus-host disease (GvHD), generally correlates with GvL, and is thus associated with an anti-leukemic response. Hence, DLT is a useful means of achieving long-term molecular remission in CML, as confirmed by EMBT studies.

The clinical efficiency of post-transplant adoptive immunotherapy was shown in EBMT trials.  This effect is more pronounced in CML, since malignant myeloid precursors supposedly produce antigen-presenting dendritic cells (DCs). Within the general mechanism of GvHD, a 'cytokine storm' may promote this type of immune response. DCs present MHC antigens to the CD8+ effector cells, thus providing them with a 'license to kill'. A clinical protocol was introduced on this basis, using a combined therapeutic schedule including GM-CSF and carefully timed DLT procedures.

A theory of evolving immune tolerance is also discussed, encompassing specific interactions between host DCs and donor CD25+ regulatory T cells. A concept of central (thymus-dependent) tolerance is developed, primarily for children undergoing therapy. Haploidentical transplants are therefore considered with respect to increased NK cell production, especially in acute lymphoblastic leukemia (ALL). A possible role of HLA mismatches and the association between chronic GvHD (cGvHD) and long-term GvL effects is discussed, such as the favorable role of cGvHD in CML, unlike ALL. Fractionation of mobilized peripheral blood cells with CD6+ cell depletion proved to be a useful immune modulation tool. 

The significance of HLA mismatches is discussed in connection with modulation of NK activity; this is presumably dependent upon specific interactions between homozygous and heterozygous immune cells, either of donor or recipient origin. 

Antiviral immunity is also discussed: in particular, generation of anti-EBV-specific cells and their in vitro and in vivo expansion, aiming for potential lymphoma prevention and control in clinical settings. 

Meanwhile, GvL is postulated to proceed either via naïve or memory T cell populations, as illustrated by cases of double cord blood transplantations. The possible mechanisms of graft-graft interactions are discussed.

Hence, adoptive immune therapy in chimeric patients should be regarded as an effective accessory tool for eradication of leukemic cells – at least in some types of leukemia.

Keywords

chronic myeloid leukemia, adoptive immune therapy, dendritic cells, T cells, HLA mismatch, immune tolerance, antiviral immunity

Other topics

Therapy of acute graft-versus-host disease

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Malte von Bonin, Martin Wermke, Uwe Platzbecker, Jörgen Radke, Nona Shayegi, Susanne Gretzinger, Konrad Heuchel, Kristina Hölig, Marc Schmitz, Gerhard Ehninger, Johannes Schetelig, Martin Bornhäuser

Medizinische Klinik und Poliklinik I, University Hospital, Dresden, Germany

Primary therapy of acute GvHD grade II–IV is still based on the systemic application of corticosteroids at doses of 1–2 mg/kg (e.g. prednisolone). Typically, investigators combine this approach with therapeutic doses of calcineurin inhibitors, which are used as prophylactic regimens. Patients not responding to steroids within 5–7 days or those with progressive disease within 72 hours represent a high-risk population that requires further immunosuppressive escalation. Pharmacological second-line therapy is mainly based on centre policies and individual decisions since no strategy has been associated with an improvement in survival within a controlled prospective trial. Compounds with efficacy in phase II trials are mycophenolate mofetil, methotrexate, pentostatin, mTOR inhibitors, antibodies targeting TNFalpha or IL-2 pathways, and monoclonal or polyclonal anti-T cell antibodies.  Non-pharmacological options include extracorporeal photopheresis and the infusion of allogeneic mesenchymal stromal cells. For most interventions, earlier treatment (e.g., within two weeks) is associated with a better outcome. However, the overall efficacy and toxicity of most approaches are unsatisfactory. Future developments include the use of regulatory T cells and more targeted approaches using small molecules interacting with specific signalling pathways of antigen-presenting and effector cells.