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Transplantation David Straus, Ph.D Transplantation David Straus, Ph.D. OBJECTIVES Understand the following: 1. The types of graft rejection 2. What are alloantigens 3. Basis for alloreactivity 4. The classes of immunosuppressive agents and how they work 5. Why a bone marrow transplant might be done, and the importance of HLA matching 6. Basis for Graft vs. Host disease 7. Problems associated with xenotransplantation REFERENCES Parham, P. Chapter 12 p. 391 - 412, 417-420 ABBREVIATIONS Human Leukocyte Antigen: HLA Major Histocompatibility Complex: MHC (mouse equivalent of HLA) T cell antigen receptor: TCR Antigen-presenting cell: APC Nuclear factor of activated T cells: NFAT Interleukin –2: IL-2 Cyclosporin A: CsA ARTICLE Bluestone, et.al. CTLA4Ig: Bridging the Basic Commentary Immunology with Clinical Application. Immunity 24, 233–238, March 2006 ª2006 Elsevier Inc. I. Introduction Transplantation of organs or tissues, to replace diseased or non-functional counterparts, has been a longstanding medical goal. Unfortunately, the immune system of the recipient usually acts as a barrier to successful transplantation. The transplanted tissue is recognized as foreign and rejected. Immunosuppressive drugs have greatly improved the outcome of transplantation procedures, though the goal of inducing tolerance to the transplanted tissue remains. Bone marrow transplantation has unique requirements for compatibility of the donor and host, and unique problems associated with the transfer of immune cells. In addition to immunity, the availability of organs for transplantation is a severe limiting factor. For this reason xenotransplantation is being explored as an option. II. Graft Rejection: Early transplant studies clearly indicated the importance of the genetic relatedness of the graft and recipient. Skin grafts within one individual were accepted, while grafts from unrelated individuals were rapidly rejected. The more closely related the donor and host, the better the chance of graft survival. Subsequent studies have described 3 characteristic types of graft rejection; hyperacute, acute and chronic rejection, and identified some of the mechanisms which are responsible. A. Hyperacute rejection is due to pre-existing antibodies in the host which recognize the graft and lead to its very rapid rejection. 1. Blood transfusions (the most common type of transplant) may be accompanied by rapid hemolysis of donor blood cells. This is mediated by pre- existing antibodies in the recipient which are reactive with erythrocyte antigens. 2. Tissue transplants: extremely rapid (within hours) rejection due to occlusion of graft vessels. Pre- existing antibodies are reactive with vessel endothelium and induce inflammatory and clotting cascades. Graft vessel occlusion is mediated by pre-existing reactive antibodies which induce inflammatory and clotting cascades. B. Acute rejection is observed 1 – 2 weeks following transplantation and is the result of a T cell-dependent adaptive immune response. Destruction of graft tissue is mediated by reactive T cells following activation by graft derived dendritic cells. C. Chronic rejection occurs months to years following transplantation and is characterized by graft vascular disease, the result of a chronic inflammatory process apparently initiated by alloantibodies. Concentric fibrosis in cardiac allograft exhibiting graft vascular disease III. Allogeneic Responses Immune-mediated graft rejection occurs as the result of recognition of antigens in the transplanted tissue as non-self antigens known as “alloantigens”. Alloantigens –differences in antigen structure between donor and recipient that are a result of genetic polymorphisms. A. Blood group antigens are glycolipid alloantigens which exist as one of three types in humans (A, B, or O). Antibodies elicited by bacterial antigens with a similar structure results in high reactivity with erthryocytes and endothelial cells which express a non-self blood group antigen. A, B, O blood group alloantigens result from differences in the carbohydrate moity of glycolipids attached to the erthryocyte cell surface. B. The highly polymorphic nature of the HLA proteins, as well as their role in activating T cells, makes them the most prominent alloantigens in transplantation. 1. HLA proteins are responsible for binding endogenous (HLA class I) and exogenous (HLA class II) antigenic peptides , and presenting them to CD8+ and CD4+ T cells. 2. HLA genes are highly polymeric Top: HLA complex genetic structure Bottom: Numbers of different HLA gene alleles found in the human population 3. HLA polymorphisms alter peptide binding and T cell recognition functions. Polymorphisms change the structure of the HLA peptide binding groove and the region contacted by the TCR. 4. Three mechanisms of HLA induced alloresponse: a. Non-self MHC (HLA) can present a novel set of peptides which may be recognized by host T cells (middle panel of figure below). b. Allotypic differences on non-self MHC (HLA) may be directly recognized by host T cells since the T cells have not been restricted during development by donor HLA (right panel; note the text indicating which MHC is self and which are nonself). c. Non-self MHC may be processed like any endogenous protein, and alloantigenic peptides presented (not shown in figure) 5. A relatively high number of T cells are able to respond to allogeneic HLA. This can be observed using the Mixed Lymphocyte Reaction (MLR) assay (Fig 5.15). C. Minor Histocompatibility antigens are non-HLA alloantigens. Many fewer T cells respond to non-HLA alloantigens and they elicit a much weaker response than allogenic HLA. However, they can be sufficient to mediate graft rejection in cases of HLA- identical transplantation. Both donor and recipient APCs can promote an alloresponse Allogeneic HLA on donor APCs may be recognized directly by recipient T cells, or “novel” peptides may be presented on donor APCs. Alternatively, donor HLA may be processed and presented on recipient APCs. IV. Improving Graft Acceptance The success rate of transplantation is improved by A. Matching HLA types (and blood groups) B. Using immunosuppressive treatment. These include relatively non- specific drugs as well as drugs or antibodies which specifically target T cells. 1. Corticosteriods a. Used in combination with cytotoxic drugs. Used acutely to stem rejection. b. Mechanism of corticosteriod action: drug binds intracellular receptor which is mobilized to the nucleus and acts as a transcriptional regulator. c. Effects are relatively non-specific- activates ~1% of all genes. d. Inflammatory response is blocked as a result of effects on cytokine production. e. Many adverse side effects: fluid retention, weight gain, diabetes, loss of bone, skin thining. Prednisone – hydrocortisone derivative, is a pro-drug; converted to its active form, prednisolone, in vivo 2. Immunosuppressive cytotoxic drugs kill dividing cells by inhibiting DNA replication (Fig 12.23). • Azathioprine: converts to thioinosinic acid, blocking purine metabolism • Cyclophosphamide: DNA alkylating agent • Methotrexate: inhibits thymidine synthesis • Cytotoxic drugs also kill non- immune cells that are dividing: effects on bone marrow, intestinal epithelium, and hair follicles, leading to anemia, thrombocytopenia, leukopenia, intestinal damage and hair loss. 3. T cell activation inhibitors: Cyclosporin A (CsA), tacrolimus (FK506), rapamycin. These drugs specifically block the activation of T lymphocytes. CsA and tacrolimus act by preventing the activation of the NFAT transcription factor and subsequent IL- 2 production. Rapamycin blocks the ability of IL-2 receptor to induce cell proliferation. The activity of the NFAT transcription factor in T cells is controlled by intracellular calcium levels and the calcineurin phosphatase. Cyclosporin A and tacrolimus bind immunophilins. These intracellular binding proteins, in complex with the drugs, target the calcineurin phosphatase and block the normal activation of the NFAT transcription factor. These drugs are relatively specific in that they target T cells, however, nephrotoxicity is associated with long term use of CsA and tacrolimus. 4. Anti-T cell antibodies are also used to treat episodes of acute graft rejection. Anti-Ig response of the patient generally limits use to a single course of treatment. C. Generating immune tolerance to the graft. Although the ability to use specific immunosuppressive drugs has made a tremendous improvement in the success of transplant procedures, generating a state of tolerance, rather than maintenance of an immunodeficient state, is the real goal for long term graft acceptance. Since T cell recognition of antigen in the absence of co-stimulatory function leads to the induction of tolerance, current approaches have focused on blocking co-stimulation. Studies using CTLA-4-Ig, a recombinant protein which is able to bind B7 ligands and prevent engagement of the CD28 co-stimulatory receptor on T cells, have shown improved allograft survival. V. Bone Marrow Transplantation Transplantation of bone marrow, or hematopoetic stem cells, has unique problems since it involves transfer of or replacement of immune system function. A. Bone marrow transplantation is used in the treatment of 1. genetic diseases of the hematopoietic system, 2. malignancies treated with ablative therapies (chemotherapy and/or radiation) which require reconstitution of the patients hematopoetic system. B. HLA matching is particularly important in bone marrow transplantation. Reconstitution of immune system function requires
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