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

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Presentation on theme: "Transplant Immunobiology Douglas Stahura DO Grandview Hospital November 6, 2002."— Presentation transcript:

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 ones 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


10 MHC HLA Class II Found on APC (antigen presenting cells) – B monocytes, macrophages, dendritic cells, mesangial cells, Kupffers cells, alveolar type 2 cells central role in the initiation of the immune response to transplantation antigens




14 T cell activation


16 Allorecognition – recognition of TRANSPLANT antigens by T cells TCR – T cell receptor recognizes MHC/antigen complex CD3 complex initiates intracellular signalling

17 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


19 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

20 T cell Costimulation


22 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

23 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

24 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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