ISSN 1866-8836
Клеточная терапия и трансплантация

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Volume 2, Number 3(7)
11/01/2011
Volume 2, Number 3(7)
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 article

Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling (1989)

Eliane Gluckman1, Hal E. Broxmeyer2, Arleen D. Auerbach3, Henry S. Friedman4, Gordon W. Douglas5, Agnes Devergie1, Helene Esperou1, Dominique Thierry6, Gerard Socie1, Pierre Lehn1, Scott Cooper2, Denis English2, Joanne Kurtzberg4, Judith Bard7, and Edward A. Boyse7

Reviews

The role of the marrow microenvironment in hematopoietic stem cell transplantation

Aravind Ramakrishnan (MD), Beverly J. Torok-Storb (Ph.D.)

Hematopoietic stem cell transplantation for metabolic storage diseases

Jakub Tolar, M.D., Ph.D.1, K. Scott Baker, M.D.2, Paul J. Orchard, M.D.1

Forum

Milestone article

Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling (1989)

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Eliane Gluckman1, Hal E. Broxmeyer2, Arleen D. Auerbach3, Henry S. Friedman4, Gordon W. Douglas5, Agnes Devergie1, Helene Esperou1, Dominique Thierry6, Gerard Socie1, Pierre Lehn1, Scott Cooper2, Denis English2, Joanne Kurtzberg4, Judith Bard7, and Edward A. Boyse7

1Bone Marrow Transplant Unit, Hôpital Saint-Louis, Paris, France; 2Departments of Medicine (Hematology/Oncology), Microbiology and Immunology, Pathology, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, USA; 3Laboratory for Investigative Dermatology, Rockefeller University, New York, USA; 4Department of Pediatrics (Hematology/Oncology), Duke University Medical Center, Durham, N.C., USA; 5Department of Obstetrics and Gynecology, New York University Medical Center, New York, USA; 6Central Nuclear Agency, Paris, France; 7Memorial Sloan-Kettering Cancer Center, New York, USA.

The clinical manifestations of Fanconi's anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents such as diepoxybutane acts as a diagnostic indicator of the genotype of Fanconi's anemia, both prenatally and postnatally [3-6]. Prenatal HLA typing has made it possible to ascertain whether a fetus is HLA-identical to an affected sibling [7].
We report here on hematopoietic reconstitution in a boy with severe Fanconi's anemia who received cryo-preserved umbilical-cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. We used a pretransplantation conditioning procedure developed specifically for the treatment of such patients [8]; this technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that cross-link DNA [9, 10] and to irradiation [11] In this case, the availability of cord blood obviated the need for obtaining bone marrow from the infant sibling.
This use of cord blood followed the suggestion of one of us that blood retrieved from umbilical cord at delivery, usually discarded, might restore hematopoiesis – a proposal supported by preparatory studies by some of us [12] and consistent with reports on the presence of hematopoietic stem and multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in human umbilical-cord blood (see the references cited by Broxmeyer et al. [12]).

Keywords

anemia, aplastic therapy, blood preservation, Fanconi anemia, female, fetal blood, HLA antigens, hematopoietic stem cell transplantation, histocompatibility testing, humans, male, pregnancy, prenatal diagnosis, preschool child

© 1989 Massachusetts Medical Society. All rights reserved.
Originally published: N Engl J Med. 1989 Oct 26;321(17):1174-8. pmid: 2571931

Reviews

Hematopoietic stem cell transplantation for thalassemia

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Surapol Issaragrisil

Bone Marrow Transplant Center, Division of Hematology, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

Hematopoietic stem cell transplantation is the only modality that offers the potential of cure for severe thalassemia, including homozygous β-thalassemia and severe Hb E/β-thalassemia. All children with class 1 or 2 disease should be transplanted if they have  HLA-identical siblings, and transplantation should be performed as early as possible. Sibling cord blood transplantation is recommended in children with class 1 or 2 of the disease if adequate numbers of cord blood cells from younger siblings are available.

Bone marrow transplantation in class 3 children and adult patients with appropriate conditioning regimen gives results that are superior to those obtained with cord blood. However, we recommend that patients and their families should discuss in detail the risks and benefits, and transplantation should be performed in only motivated patients who have a clear understanding of the entire process. There is new hope that haploidentical transplantation will be successful, but further studies are required to confirm early results.

Keywords

thalassemia, clinical risk factors, hematopoietic stem cell transplantation, indications, benefits

Reviews

The role of the marrow microenvironment in hematopoietic stem cell transplantation

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Aravind Ramakrishnan (MD), Beverly J. Torok-Storb (Ph.D.)

Fred Hutchinson Cancer Research Center and the University of Washington, Seattle, USA

The success of hematopoietic stem cell transplantation depends on the engraftment of pluripotent hematopoietic stem cells and the regulated proliferation and maturation of committed progenitor cells. It is generally agreed that these processes cannot occur without an appropriate milieu provided by a competent marrow microenvironment (ME). The ME is composed of both non-hematopoietic and hematopoietic stem cell derived cells and consequently is chimeric following allogeneic stem cell transplantation, containing recipient stromal cells and donor macrophages.

Keywords

hematopoietic microenvironment, stromal cell, transplantation, stem cell niche, ME units, monocyte/macrophage

Reviews

Hematopoietic stem cell transplantation for metabolic storage diseases

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Jakub Tolar, M.D., Ph.D.1, K. Scott Baker, M.D.2, Paul J. Orchard, M.D.1

1Division of Hematology/Oncology and Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, USA; 2Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Almost thirty years of hematopoietic cell transplantation for congenital enzymopathies have revealed that the transfer of relatively few hematopoietic stem cells is able to fully reconstitute the lymphohematopoietic system in conditioned recipients and to maintain long term complementation of the enzyme defect in the recipient. Despite decades of effort to illuminate the mechanisms whereby the cross correction occurs, it remains unclear why hematopoietic cell transplantation is adequate only in some enzyme deficiencies. Here we review both biochemical and clinical data on the metabolic storage diseases in which the natural history and quality of life have been changed after hematopoietic cell transplantation. The challenge ahead is to understand the pathophysiology of congenital enzymopathies resistant to correction with hematopoietic cell transplantation, and to test whether the advances in stem cell therapy and gene correction can be translated into less toxic and even more effective therapy of metabolic storage diseases for which hematopoietic cell transplantation is a standard of care today.

Keywords

hematopoietic cell transplantation, conditioning regimen for hematopoietic cell transplantation, mucopolysaccharidosis, Hurler syndrome, metachromatic leukodystrophy, globoid cell leukodystrophy, Krabbe disease, adrenoleukodystrophy, mannosidosis, late effects after hematopoietic cell transplantation

Reviews

Hematopoietic cell transplantation for treatment of primary immune deficiencies

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Lauri Burroughs (MD), Ann Woolfrey (MD)

Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA

Hematopoietic cell transplantation (HCT) has the potential to cure primary immune deficiency syndromes (PIDS) that are a group of disorders primarily affecting a single lineage, e.g., lymphoid or myeloid lineage. Generally, implementation of various conditioning regimens depends the type of IDS. Some syndromes that cause profound immune deficiency may not require a conditioning regimen. There appears to be a barrier even in cases of severe combined immune deficiency (SCID), particularly in the situation of HLA mismatched or haploidentical grafts. For example, donor B cell chimerism is less likely in γ-chain deficiency (X-SCID), as host cells persistently occupy the B lymphocyte niche, than in syndromes without B cells such as adenosine deaminase (ADA) deficiency. The immune defect may be corrected by partial reconstitution of normal immune cells, in other words full donor chimerism of the affected cell subset may not be required. This concept may add further rationale to limiting the intensity of the conditioning regimen.

SCID encompasses a broad range of inherited defects that individually cause a profound immune deficiency of both T and B cell function. The individual genetic defects give rise to various phenotypes, and, since the goal of HCT is to restore both T and B cell function, the SCID phenotype must be taken into consideration in addition to the degree of recipient-donor mismatch. Other biologic factors associated with the SCID phenotype may influence the barrier to engraftment, such as host NK cells, which may survive intensive conditioning regimens. One of the difficulties in analyzing outcome of HCT in SCID patients is the relative rarity of the condition, thus needing large multicentric studies. Recent studies show that the most important factor for improved survival after an HLA-identical sibling graft was younger age at time of HCT. Factors significantly associated with improved survival after haploidentical transplants were B+ SCID phenotype, protected environment, and lack of pulmonary infections before HCT. The advent of neonatal screening and in utero diagnosis has allowed early detection of SCID and therefore prompt intervention at an early age.

Primary T cell immunodeficiency (PTCD) syndromes may be differentiated from SCID by virtue of reduced but not completely absent T cell function, or absent T cell function with the presence of B lymphocyte or NK cell function. Allogeneic marrow transplantation remains the only curative therapy available for these disorders. Worse outcomes were seen in patients with PTCD compared to other types of immune deficiencies, regardless of donor. Although life-threatening infections may be less common early in life, children with PTCD often develop organ damage from chronic infections, particularly lung disease, prior to HCT.

In Wiskott-Aldrich syndrome, HCT offers significantly improved survival chances for patients. Achieving full donor chimerism was shown to be a favorable factor. In general, however, the studies suggest that low intensity regimens offer the potential for achieving donor cell engraftment with less morbidity than standard regimens, an important consideration for patients who currently may consider the risks of conventional transplants unacceptably high.

Keywords

Primary immune deficiencies, SCID, primary T cell deficiencies, hematopoietic stem cell transplantation, conditioning regimens, outcomes

Reviews

Hematopoietic cell transplantation for autoimmune diseases

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Richard A. Nash, MD

Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, WA, USA

Autoimmune diseases may or may not have defined antigenic targets and may involve single or multiple organs. Although most autoimmune diseases can be effectively managed even if not cured, some autoimmune diseases may be refractory to conventional treatments and become life-threatening or cause critical organs to fail. This then would be the candidate population for consideration of a more aggressive approach requiring autologous or allogeneic hematopoietic cell transplantation (HCT). The clinical trials of HCT for autoimmune disease were started more than a decade ago and were based on successful preclinical studies. Preclinical studies of autologous and allogeneic HCT for autoimmune diseases have been reviewed and will not be discussed further [1, 2].

Keywords

autoimmune diseases, systemic sclerosis, multiple sclerosis, hematopoietic cell transplantation

Reviews

Graft-versus-host disease: from experiments to clinical insight

Hans-Jochem Kolb

Kolb Consulting UG, Senior Consultant, 3. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Germany

Correspondence
Kolb Consulting UG, Senior Consultant, 3. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Germany
E-mail: h-j-kolb@spam is badweb.de

The pathophysiology, prevention, and treatment of acute graft-versus-host disease (GVHD) occurring, mainly, after allogeneic hematopoietic stem cell transplantation (allo-HSCT), should be understood, in order to exploit its potential benefits while avoiding certain clinical risks. Many studies have shown haematopoietic cells to be primary targets, as well as skin, gut, and liver containing macrophage-derived cells. The latters produce pro-inflammatory cytokines that stimulate donor T cells and induce HLA class II antigens in host tissue. Dendritic cells (DCs) boost CD 8 cells to react against HLA class I peptides. Hence, GVH reactions of the graft are directed against histocompatibility antigens of the recipient that are foreign to the donor. Polymorphic non-HLA proteins may also cause severe GVH reactions. The reactions against minor histocompatibility antigens require a longer phase of activation than reactions against MHC antigens. 

The preconditions of acute GVHD (aGVHD) are given before transplantation (the s.c. “cytokine storm” liberated by intensive conditioning treatment and probable infections). However, in human patients, donor lymphocyte transfusion may produce GVHD without conditioning treatment. In general, the host’s immune system is continuously suppressed by the graft and; the graft becomes tolerant towards the host. The mechanism of tolerance has been related to the occurrence of non-specific and specific suppressor cells followed by clonal deletion, being also mediated by mesenchymal stromal cells, NK-T cells, and regulatory T cells. Selecting an HLA-identical sibling as donor was the major step towards successful HSCT (generally, definition of 10 HLA-loci is required to prevent severe GVHD). Several TNF-a and TNF-a receptor alleles are associated with an increased risk of GVHD. The well-known clinical features of aGVHD are also described, including skin, liver, and gut lesions. The issues of chronic GVHD are also described. Its clinical and pathological signs resemble autoimmune diseases in many aspects. 

GVHD prophylaxis is well established, and should be used in any clinical setting. Special attention is given to T cell depletion and modern immunosuppressive therapies post-transplant. Current schedules of GVHD treatment are described including calcineurin inhibitors, and some novel suppressive drugs. The role of various treatment regimens is considered in view of regulatory T cell (Treg), mesenchymal stem cells and UV-A irradiation as possible means of GVHD management. 

Special attention is drawn to induction of a graft-versus-host tolerance in clinical HSCT. In the majority of patients, the peripheral (thymus-independent) form of tolerance prevails. Specific selective effects of Rapamycin upon T cells are discussed.

Keywords

graft-versus-host disease, prophylaxis, treatment, conditioning therapy, dendritic cells, Т-lymphocytes, immune suppression, immune therapy

Reviews

Umbilical cord blood transplantation for treatment of non-malignant disorders

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Mitchell E. Horwitz (MD), Nelson Chao (MD, MBA)

Division of Cellular Therapy, Duke University Medical Center, Durham, North Carolina, USA

As the outcomes of umbilical cord blood transplantation improve, the risk versus benefit considerations with respect to treatment of non-malignant disorders must be reassessed. Recent data would suggest that the outcome of umbilical cord blood transplantation is comparable to that of matched unrelated donor transplantation. Thus, patients felt not to be candidates for this potentially curative treatment modality due to lack of an available matched donor should be considered for matched or mismatched unrelated umbilical cord blood transplantation. This review will cover the most recent data pertaining to umbilical cord blood transplantation for the treatment of congenital immunodeficiency disorders, inborn errors of metabolism, bone marrow failure disorders, and hemoglobinopathies.  

Keywords

stem cell transplantation, umbilical cord blood, outcomes, clinical results, immunodeficiency, non-malignant disorders, bone marrow failure, review

Forum

Scientific blogging as a model for professional networking online

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Alexey Bersenev, MD, PhD

314G Abramson Research Center, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

Scientific blogging is a relatively new kind of activity that scientists and people related to science do online. In this essay I’m sharing my own experience about how scientific blogging could be used to establish and advance your professional networking online. The model I use proposes blogging analytical content in a precise scientific niche and sharing discussion and expert opinions through web tools. I use a blog as a central hub for analysis of information flowing from my personal filters and for setting up collaborative filters online, based on professional trusted content. Overall, I think a blog could be one of the best web tools for scientists to build a professional network online.

Keywords

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science online, Web 2.0, blog, scientific blogging, networking

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Online medical content curation and personal time management with Web 2.0: an exciting era

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Bertalan Mesko, MD

Managing director of Webicina.com

The recent increase in the number of online medical resources has raised important questions about content curation on the World Wide Web and the importance of time management tools and applications used in medicine and healthcare. Content curation is crucial at a time when patients and their doctors are searching more online but the majority of health resources are considered medically unreliable. The value of crowdsourcing and time management tools that can save time and effort for professionals is demonstrated.

Keywords

Internet, content curation, time management, Web 2.0