Elsevier

Autoimmunity Reviews

Volume 5, Issue 3, March 2006, Pages 167-179
Autoimmunity Reviews

Hematopoietic stem cell transplantation (HSCT): An approach to autoimmunity

https://doi.org/10.1016/j.autrev.2005.06.003Get rights and content

Abstract

HSCT provides the opportunity to replace a damaged tissue. It is the most important treatment for high risk hematologic malignant and non malignant disorders. An important challenge in the identification of matched donors/patients is the HLA diversity. The Mexican Bone Marrow Registry (DONORMO) has nowadays > 5000 donors. The prevalent alleles are Amerindian, Mediterranean (Semitic and Spanish genes) and African. In theory, it is possible to find 11% of 6/6 A–B–DR low resolution matches for 70% of patients with Mexican ancestry. We contributed with 39 unrelated, cord blood and autologous HSCT for patients with malignant, genetic and autoimmune disorders. Overall disease survival was 50% (2–7 years) depending on the initial diagnosis, conditioning, disease evolution or other factors. Clinical studies using autologous and unrelated HSC are performed on patients with refractory autoimmune diseases producing mixed results: mainly, T1D, RA, MS, SLE. Improvement has been observed in skin damage and quality of life in SLE and systemic sclerosis. Disease stabilization in 2/3 of MS patients. However, in RA and T1D, initial benefits have been followed by eventual relapse. With growing clinical experience and protocol improvement, treatment-related mortality is decreasing. Proof efficacy will be achieved by comparing HSCT with standard therapy in 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

  • The Major Histocompatibility Complex plays a central role in allogeneic HSCT

  • Minor Histocompatibility Antigens, NK cells and KIR genes are important for HSCT outcome

  • Engraftment, rejection, GVHD, GVL, infections and drug toxicity are relevant influences in transplantation

  • Animal models have been the key to understand the biological and molecular

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