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Transplantation: Types of Graft Rejection, Alloantigens, and Immunosuppressive Agents

Learn about the types of graft rejection, alloantigens, and the classes of immunosuppressive agents. Understand the importance of HLA matching in bone marrow transplants and the basis for graft vs. host disease. Explore the problems associated with xenotransplantation.

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Transplantation: Types of Graft Rejection, Alloantigens, and Immunosuppressive Agents

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  1. 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 in bone marrow transplants • 6. basis for graft vs. host disease • 7. problems associated with xenotransplantation • Parham, P. Chapter 12 p. 391 - 412, 417 - 420

  2. Types of graft rejection Hyperacute - extremely rapid rejection (hours) occlusion of graft vessels initiated by pre-existing antibodies Acute - days to weeks after transplant adaptive immune response Chronic -months to years after transplant graft vascular disease

  3. Alloantigens and alloreactivity Recognition of structural differences (in “self”-antigens) Example:Blood group Ag- difference in carbohydrate structure Allelic differences in self-antigens can lead to alloreactivity Highly polymorphic genes are a likely source of alloantigens HLA-dependent alloreactivity HLA as an alloantigen Direct HLA recognition by recipient T cell repertoire Recognition of new spectrum of self-peptides presented by donor HLA Minor Histocompatibility antigens - difference in self-antigen structure, but not HLA.

  4. Both donor and recipient APCs can present alloantigens to recipient T cells Allogeneic HLA may be recognized directly on donor APCs, or may present “novel” peptides. Additionally, allogeneic HLA, like other alloantigens, may be processed and presented on recipient APCs.

  5. Improving graft acceptance HLA matching Immunosuppressive drugs Corticosteroids: prednisone- block production of inflammatory cytokines Cytotoxic drugs: cyclophosphamide, azathioprine, methotrexate, kill dividing cells, including lymphocytes, by targeting DNA replication Specific immunosuppressants: cyclosporin A, FK506/tacrolimus, rapamycin target T cell activation process Tolerance induction: reagents to block T cell co-stimulation (CTLA4Ig)

  6. Bone Marrow transplantation Hematopoietic reconstitution for genetic or malignant disease Special issues HLA matching critical for reconstitution of immune function Graft vs. Host disease: systemic alloreaction of donor T cells to host tissue damage of host tissue by pre-transplant therapy is associated with GVHD Graft vs. Leukemia effect GvH disease has the benefit of helping eliminate residual tumor cells as a result of alloreactivity

  7. Reconstitution of a functional immune system requires sharing of some HLA haplotypes: T cell selection in the host thymus determines recognition of donor APCs

  8. Xenotransplantation • Why pigs? • non-primates with organs of similar size to humans. • can make transgenic pigs to address some cross-species problems • Problems • Hyperacute rejection by pre-existing xenoantibodies. Complement inhibitory proteins are unable to function across • a large species gap which increases hyperacute rejection. • A potential risk of transferring cross-species pathogens under immunosuppressive conditions

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