Major Histocompatibility Complex (MHC)

1. Major Histocompatibility Complex(MHC) • What is MHC? • HLA • H-2 (in the mouse) • Minor histocompatibility antigens

2. There may be polymorphic antigens other than MHC that differ between the donor and the recipient. • These antigens induce weak or slower ( more gradual) rejection reactions than do MHC molecules and are called Minor histocompatibility antigens.

3. Minor histocompatibility antigens are proteins that are processed an presented to host T cells association with self MHC molecules on host APCs (by indirect pathway).

4. Significance of the MHC • role in immune response • role in organ transplantation • role in predisposition to disease

5. Genetic barriers to transplantation • autologous: in the same individual (autograft) • isologous: between genetically Identical individuals (isograft), i.e., identical twins (inbred animals) • homologous: between individuals of the same species (allograft) • heterologous: between individuals different species (xenograft)

6. Principles of transplantation

7. Minor histocompatibility antigensand graft survival • minor histocompatibility antigens also cause rejection • The rejection time is variable but longer than that for major histocompatibility antigen • They have additive effects

8. Graft versus host (GVH) disease

9. GVH disease in humans

10. The human MHC genes

11. The mouse MHC genes

12. Polymorphism of MHC antigens (based on phenotype)

13. Polymorphism of MHC genes(based on DNA sequence/ PCR)

14. MHC products expressed on cells If Jack and Jill have four children; Bo, Kim, Mo and Lee They’ll all inherit antigens of the parental MHC Oft their haplotypes will be of the father or mother Unless during meiosis, a crossover should occur

15. The inheritance of MHC genes

16. MHC products expressed on cells

17. Crossing overresults in new haplotypes

18. Differential expression of MHC antigens • Class-I expressed on all nucleated cells in man, and also on erythrocytes in mice. • Class-II expressed primarily on antigen presenting cells (dendritic cells, macrophages and B cells, etc.)

19. CD4+TH1 CD8+preCTL CD8+CTL Alloreactivity of T cells: MLR and CTL generation

20. Alloreactivity of T cells Alloreaction (MLR) Thymus Positive Selection Proliferation and Differentiation

21. TNF, NO2 IL2, TNF, IFN  IL2, IL4, IL5 lysis IL2, IFN  Mechanisms of graft rejection Inflammation ADCC lysis rejection

22. type of rejection cause time taken minutes- hours preformed anti-donor antibodies and complement hyperacute reactivation of sensitized T cells (secondary response) days accelerated primary activation of T cells acute days-weeks unclear causes: cross reactive Ab, immune complexes, slow cellular reaction, tolerance breakdown, disease recurrence months-years chronic Tempo of rejection reaction

23. agent mode of action application(s) organ transplant, hypersensitivity, autoimmunity organ transplant, corticosteroids, prednisone cyclosporine, ticrolimus anti-inflammatory, altering T-cell and PMN traffic inhibition of IL-2 production by T cells Inhibition of T cell activation by IL-2 organ transplant rapamycin Immunosuppressive agents

24. agent mode of action application(s) purine metabolism organ transplant azathioprine, 6-MP organ transplant methotrexate folate metabolism autoimmune diseases, organ transplant cyclophosphamide, melphalan alkylation of DNA, RNA and proteins x-irradiation Lymphopenia malignancy/marrow transplantation Immunosuppressive agents

25. Magnet Removal of T cells from marrow graft Magnetic antibodies

26. HLA and disease association