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Transplant Immunobiology

Transplant Immunobiology. Douglas Stahura DO Grandview Hospital November 6, 2002. Goals. Review definitions Review basic mechanisms of immunologic system Understand T-cell immunity Review transplant medications and mechanisms. Definitions.

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Transplant Immunobiology

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  1. Transplant Immunobiology Douglas Stahura DO Grandview Hospital November 6, 2002

  2. Goals • Review definitions • Review basic mechanisms of immunologic system • Understand T-cell immunity • Review transplant medications and mechanisms

  3. Definitions • Autograft – transplantation of one’s own tissue to another site • Syngraft – transplantation of graft between two genetically identical individuals • Allograft – transplantation of graft between individuals of the same species • Xenograft – transplantation of graft between individuals of different species

  4. Definitions • Alloantigens – antigens recognized as foreign on allografts • Alloreactive – lymphocytes that recognize and respond to alloantigens

  5. Definitions • Major Histocompatibility Complex (MHC) • In humans, known as HLA system • Central role in antigen recognition • Principal immunologic function of MHC gene product is to present antigens as fragments of foreign proteins, forming complexes that can be recognized by T lymphocytes

  6. MHC • MHC molecules are membrane associated • Antigen-specific T lymphocytes recognize fragments of antigens only when bound to the surface of other cells that bear MHC molecules • Mature T lymphocytes recognize and react to foreign antigens and not to self • Clonal deletion • Self tolerance

  7. MHC • Located on short arm of chromosome 6 • Six separate genes; • Class I = HLA-A,B,C • Class II = DR,DQ,DP • Each gene is represented by one of two codominant alleles (paternal +maternal) • Haplotype – alleles of HLA system passed to offspring via meiosis

  8. MHC • HLA Class I • Found on all nucleated cells • Function as immunorecognition site for endogenously synthesized foreign protein antigens • Recognized by CD8+ T cells

  9. MHC • HLA Class II • Found on APC (antigen presenting cells) • B monocytes, macrophages, dendritic cells, mesangial cells, Kupffer’s cells, alveolar type 2 cells • central role in the initiation of the immune response to transplantation antigens

  10. T cell activation

  11. T cell activation Allorecognition – recognition of TRANSPLANT antigens by T cells TCR – T cell receptor “recognizes” MHC/antigen complex CD3 complex initiates intracellular signalling

  12. T cell activation • CD3 complex – five peptide chain closely arrayed in cell membrane alongside TCR • TCR binding induces conformational change in CD3 which initiates intracellular signal pathways

  13. T cell activation • Accessory molecules • Stabilize the interaction between cytotoxic T cells and their target cell • Provide a non-antigen “second” signal for T cell activation • Adhesion molecules enhance antigen recognition by increasing affinity between T cell and MHC cell • TCR recognition without accessory molecule co-stimulation results in clonal anergy or apoptosis

  14. T cell Costimulation

  15. Immunosuppressive Medications • Drugs target the cellular mechanisms that are known • Signal ONE • Calcineurin inhibitors • Cylosporine (Sandimmune, Neoral) • Tacrolimus (FK506, Prograf) • Monoclonal Antibodies • OKT3 – targets CD3 molecule • Polyclonal Antibodies (ALG) • Thymoglobulin

  16. Immunosuppressive Medications • Signal Two – no currently approved • Signal Three • Sirolimus (Rapamycin) • Monoclonal Ab that target IL-2 receptors • Anti-metabolite • Azathioprine (Imuran) nonspecific inhibitor of purine synthesis • Mycophenolate mofetil (Cellcept) lymphocyte selective inhibitor of de novo purine synthesis

  17. Immunosuppressive Medications • Corticosteroids • Blocks T-cell and APC cytokine and cytokine receptor expression (inhibits transcription) • Blocks migration of lymphocytes to tissues (anti-inflammatory)

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