Hematopoietic stem cell transplantation (HSCT): An approach to autoimmunity
Introduction
Immunology plays a central role in allogeneic HSCT. This treatment was developed as a strategy to prevent the bone-marrow toxicity that is caused by intense chemotherapy regimens and it cures a significant percentage of patients who have otherwise fatal hematologic malignancies. Reciprocal immune reactions between donor and recipient are a major feature of allogeneic HSCT and have both, deleterious (GVHD—graft versus host disease) and beneficial consequences (GVL—graft versus leukemia effect). Other immunological mechanisms involved in engraftment, control of malignancy, the development of tolerance and immune reconstitution requires understanding of the immunogenetic basis for immune reactions provoked by grafting tissue from one individual to another [1].
Section snippets
Major histocompatibility antigens
The Major Histocompatibility Complex (MHC) is the most important genetic region in the human genome in relation to infection, autoimmunity and transplantation. The HLA complex (Human Leukocyte Antigens) map of the human extended MHC (xMHC) is located on chromosome 6 from centromere to telomere and spans about 8 Mb. The xMHC harbors six gene clusters (solute carrier 17A, vomeronasal receptor, tumor necrosis factor, lymphocyte antigen-6, heat shock protein, class II) and six superclusters
Difference in response against major and minor antigens
Immune response against HLA differs greatly from responses against mHA. The precursor frequency of T-cells that respond to any given HLA antigen is as high as 1–10%. Generation of an in-vivo response against mHA requires in-vivo priming with mismatched cells for mHAs; the precursor frequency of T-cells to MHC identical stimulators with disparity for multiple MHA after priming, has been estimated at is 0.01–0.10%. The MHA do not generally induce alloimmune antibody responses detectable by
The HLA barrier
In unrelated donor HSC, the major challenge to successful outcome is the need to overcome host vs. graft and the GVH immunogenic reaction that leads to rejection or to GVHD. A deep understanding of the MHC is also needed, because its function extends to the development of tolerance, immune reconstitution and in the establishment of GVL. As of May 2005, over nine and a half million registered volunteer bone marrow donors existed in 54 registries worldwide. Many registry data indicate that a
Historical perspective
The hypothesis that HSCT might be useful in treating refractory autoimmune diseases (AD) was suggested by studies in animal models and by the improvement or even full remission of concurrent AD in patients who also have undergone transplantation for hematologic disorders [23]. On the contrary there have been reports of transfer of AD, from disease affected allogeneic HSC donors into previously unaffected recipients. It is important to bear in mind that heterogeneity exists among the
Conclusions
Clinical HSCT has evolved from the biomedical knowledge and understanding gained from animal models that had unraveled to us many of the immunological mechanisms involved in rejection, GVHD, GVL, tolerance induction and certainly because models for several human AD have shown the interaction between genetics and environment. Murine models have the advantage of clear defined immunogenetics and an enormous treasure for dissecting the cellular and humoral mechanisms involved in HSC transplantation
Acknowledgement
This study was done greatly with the support of The Fundación Comparte Vida, A.C. Foundation that supports DONORMO & BACECU in Mexico.
Take-Home Messages
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The Major Histocompatibility Complex plays a central role in allogeneic HSCT
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Minor Histocompatibility Antigens, NK cells and KIR genes are important for HSCT outcome
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Engraftment, rejection, GVHD, GVL, infections and drug toxicity are relevant influences in transplantation
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Animal models have been the key to understand the biological and molecular
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2024, Advanced Drug Delivery ReviewsAutologous hematopoietic stem cell transplantation in Systemic Lupus Erythematosus and antiphospholipid syndrome: A systematic review
2017, Autoimmunity ReviewsCitation Excerpt :The initial findings of remission of severe autoimmune disease were described in patients undergoing transplantation for a hematologic disease who also had a coincidental autoimmune disease [4–6]. Following these observations, this therapeutic approach has been applied to other severe autoimmune diseases refractory to standard therapy [7–10] and preliminary results of animal model studies have been promising [11,12]. Although the mechanism of remission of disease induced by HSCT is likely to be due to intensive immune suppression, it may also play a role in modifying the immune system after transplant and thus leading to a prolonged period of remission.
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2015, Journal of Medical Imaging and Radiation SciencesCitation Excerpt :Over the past 30 years, total body irradiation (TBI) has become an integral part of haematologic stem cell transplant (HSCT) or bone marrow transplant (BMT) preparative regimes [1–3]. HSCT protocols have been developed to focus on the treatment of a variety of oncologic, immunologic, or haematologic diseases, including primarily acute leukaemias, non-Hodgkin lymphoma, and aplastic anaemia [4–6]. Although HSCT was originally designed for the treatment of palliative lymphoma patients in the 1970s, utilisation has become increasingly popular because of the benefit of myeloablative effects on patients and increased radiosensitivity of these diseases [3].
Adipose-derived stem cells induced dendritic cells undergo tolerance and inhibit Th1 polarization
2012, Cellular ImmunologyCitation Excerpt :Its rationale is based on eliminating autoaggressive lymphocytes by lympho- or myeloablative conditioning followed by stem-cell rescue [11–13]. Preclinical studies in animal models of autoimmune disease and observations in patients with rheumatoid arthritis (RA) who were cured after allogeneic bone marrow transplantation for concomitant hematologic malignancy have provided support for the concept [14–16]. However, the immune property of ADSC is still unknown.
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2006, Gastroenterologia y Hepatologia Continuada