Transplantation immunology

Transplantation immunology

1. WELCOME

2. Transplantation immunology

3. Content Introduction. Types of transplants. Specificity & memory of the rejection responses. Role of cell mediated responses. Transplantation antigens. Tissue typing. Immunology of transplant rejection. Clinical manifestation of graft rejection. Immunosuppressive therapy. Conclusion. References.

4. Introduction Transplantation- the act of transferring cells, tissues, or organs from one site to another. The individual who provides the graft is called the Donor, and the one who receive the graft is called either the recipient or the host. Transfusion is the transplantation of circulating blood cells or plasma from one individual to another. A major limitation to the success of transplantation is the immune response of the recipient to the donor tissue.

5. Types of Transplant Autograft is self-tissue transferred from one body site to another in the same individual. Isograft is tissue transferred between genetically identical individuals. Allograft is tissue transferred between genetically different members of the same species. Xenograft is tissue transferred between different species.

6. Specificity and memory of the rejection response The time sequence of allograft rejection varies according to tissue involved. Graft rejection always displays the attributes of specificity and memory.

7. Fig-Schematic diagrams of the process of graft acceptance and rejection.

8. Role of cell-Mediated responses Lymphocytes, but not serum antibody, could transfer allograft immunity ( 1950s by Avrion Mitchison ) T-cells derived from an allograft-primed mouse were shown to transfer second-set allograft rejection to an unprimed sygeneic recipient , as long as that recipient was grafed with the same allogeneic tissue. Analysis of the T-cell subpopulations involved in allograft rejection has implicated both CD4 + and CD8 + populations.

9. Experimental demonstration Both CD4+ and CD8+ T-cells participated in rejection and that the collaboration of both subpopulation resulted in more pronounced graft rejection.

10. Role of CD4 & CD8 T-cells in allograft rejection

11. Transplantation Antigens Tissue that are antigenically similar are said to be Histocompatible . Tissues that display significantly antigenic differences are Histoincompatible , such tissues do induce an immune response that leads to tissue rejection Encoded by more than 40 different loci. MHC inheritance in outbred population is more complex.

12. TISSUE TYPING ABO blood-group compatibility. HLA typing Microcytotoxicity test Mixed-lymphocyte reaction (MLR)

13. Microcyto -toxicity method

14. MLR

15. Immunology of Transplant Rejection Components of the Immune system involved in graft Rejection : 1) Antigen presenting cells – Dendritic cells Macrophages Activated B Cells 2) B cells and antibodies – Natural antibodies Preformed antibodies from prior sensatization Induced antibodies 3) T cells 4) Other cells – Natural killer cells T cells that express NK cell – associated Markers Monocytes /Macrophages

16. The Immunology of Allogeneic Transplantation Recognition of transplanted cells that are self or foreign is determined by polymorphic genes (MHC) that are inherited from both parents and are expressed co-dominantly. Alloantigens elicit both cell-mediated and humoral immune responses.

17. Recognition of Alloantigens Direct Presentation Recognition of an intact MHC molecule displayed by donor APC in the graft Basically, self MHC molecule recognizes the structure of an intact allogeneic MHC molecule Involves both CD8 + and CD4 + T cells.

18. . Indirect Presentation Donor MHC is processed and presented by recipient APC Basically, donor MHC molecule is handled like any other foreign antigen Involve only CD4+ T cells. Antigen presentation by class II MHC molecules.

19. The process of graft rejection can be divided into two stages- An effector stage Sensitization phase

20. Sensitization stage CD4 & CD8 T-cells recognize alloantigens expressed on cells of the foreign graft & proliferate in response. Both dendritic cells & vascular endothelial cells from an allogeneic graft induce host T-cell proliferation. The degree & type of immunologic response varies with the type of transplant.

21. Effector stage A variety of effector mechanisms participate, these are cell-mediated reactions involving delayed-type hypersensitivity & CTL-mediated cytotoxicity (most common). Less common mechanisms are- Ab plus-complement lysis . Destruction by ADCC. Involves influx of T-cells & macrophages into the graft. Cytokines secreted by T H cells play a central role.

22. Effector mechanism involved in graft rejection

23. Role of Cytokines in Graft Rejection IL – 2 , IFN –  , and TNF -  are important mediators of graft rejection. IL – α promotes T-cell proliferation and generation of T – Lymphocytes. IFN -  is central to the development of DTH response. TNF -  has direct cytotoxic effect on the cells of graft. A number of cytokines promote graft rejection by inducing expression of class – I or class – II MHC molecule on graft cell. The interferon (α,  and  ), TNF – α and TNF -  all increases class – I MHC expression, and IFN -  increases class – II MHC expression as well.

24. Clinical manifestations of graft rejection Hyperacute rejection Caused by preexisting host serum Abs specific for antigens of the graft. Activates complement cascade.

25. Acute rejection- Cell mediated allograft rejection. begins about 10days after transplantation. Massive infiltration of macrophages & lymphocytes at site of tissue destruction. T H cell activation and proliferation.

26. Chronic rejection Develop after months or years after transplantation. Include both humoral & CMI response by recipient. Not prevented in most cases. Difficult to manage with immunosuppressive drugs.

27. General immunosuppressive therapy Allogeneic transplantation requires some degree of immunosuppression if transplant is to survive. Mitotic inhibitors- Azathioprine , Cyclophosphamide , Methotrexate Corticosteroids- Prednisone, Dexamethasone , Cyclosporin A, FK506, Rapamycin . Total lymphoid irradiation- 200rads/day.

28. Specific immunosuppressive therapy Monoclonal antibody therapy- Monoclonal antibody directed against various surface molecules on cells of immune system. Use of monoclonal antibody to CD3 molecule of TCR complex. Cytotoxic agent such as Diphtheria toxin coupled with antibody. Use of monoclonal antibody specific for high affinity IL2 receptor. Anti-CD4 monoclonal antibody.

29. . Cell surface adhesion molecules Monoclonal antibodies to adhesion molecules ICAM1 & LFA-1 Monoclonal antibodies specific for cytokines. Monoclonal antibodies to TNF- . Monoclonal antibodies to IFN ϒ & IL2. Agents that block co-stimulatory signals By interaction of B7 molecules on the membrane of APC with CD28 or CTLA-4 molecule on T-cells. Interaction of CD40 (present on APC) & CD40 ligand (present on T-cells)

30. Blocking co-stimulatory signals (a) (B)

31. Tissue and Organ Transplantation Today it is possible to transplant many different organs and tissues including. Most common transplantation is blood transfusion. Bone Marrow transplantation Organs : Heart, kidneys, pancrease , lungs, liver and intestines. Tissues : include bones, corneas, skin, heart values, veins, cartilage and other connective tissues.

32. Clinical transplantation

33. Conclusion More than 50,000 people, waiting for compatible donor. For ethical an practical reasons, species closely related to human such as Chimpanzee have not been widely used. Xenogeneic transplantation may be major issue of research xenograft technology including genetically modified animal may become a new source of organ supply. Side effects of immunosuppressive agent use for graft need a change of specificity in action and avoiding general immune suppression. Techniques such as transgenic animal production and wide range of research in this field hope to result in opening a new window for the process of transplantation immunology.

34. References Kuby immunology (4 th edition), Richard A. Goldsby , Thomas J. Kindt , Barbara A. Osborne. Cellular & molecular immunology (5 th edition), Abdul K. Abbas , Andrew H. Lichtman . Immunology (6 th edition), Ivan Roitt , Jonathan Brostoff , David Male.

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