1. ORGAN TRANSPLANTATION Replacement of diseased, demaged or worn-out organs

2. REQUIREMENTS * Introduce a transplant in a way that allows it to function normally. * Maintain the health of both the recipient and the transplant. * Prevent an adaptive immune reaction by the host, against the graft- done by non- specific immunosuppression. (immunosuppressive drugs + antibodies) ORGAN TRANSPLANTATION

3. Major tissues and organs transplanted Thoracic organs heart lung heart/lung Abdominal organs kidney liver pancreas intestine Tissues, cells and fluids cornea Islets of Langerhans bone marrow blood transfusion heart valve bone

4. Examples

5. History of transplantations 1905: First successful cornea transplant (Czech Republic) 1950: First successful kidney transplant (Chicago, U.S.A) [9] [9] 1966: First successful pancreas transplant (Minnesota, U.S.A.) 1967: First successful liver transplant (Denver, U.S.A.) 1967: First successful heart transplant (Cape Town, South Africa) 1981: First successful heart/lung transplant (Stanford, U.S.A.) 1983: First successful lung lobe transplant (Toronto, Canada) 1998: First successful live-donor partial pancreas transplant (Minnesota, U.S.A.) 1998: First successful hand transplant (Lyon, France) 1999: First successful Tissue Engineered Bladder transplanted (Boston Children's Hospital, U.S.A.) 2005: First successful ovarian transplant (Wadia hospital Mumbai, India) 2005: First successful partial face transplant (France) 2008: First successful complete full double arm transplant (Technical University of Munich, Germany) 2008: First baby born from transplanted ovary by James Randerson 2008: First successful transplantation of near total area (80%) of face, (including palate, nose, cheeks, and eyelid) (Cleveland, USA) 2010: First full facial transplant (Hospital Universitari Vall d'Hebron on July 26, 2010 in Barcelona, Spain.) 2011: First double leg transplant (Valencia's Hospital La Fe, Spain)

6. Basic concepts in transplantation Allotransplantation (Allo- meaning “other”) is the transplantation of cells, tissues or organs to a recipient from donor of the same species. The transplant is called allograft. Alloreaction is directed against transplantation antigens. Transplantation antigens can be: Major- encoded by classical MHC genes Manor- any polymorphic genes encoding peptides, in the context of MHC Blood group antigens are considered as transplantation antigens To prevent an alloreaction the patients are given a variety of immunosuppressive drugs and antibodies that prevent the activation and proliferation of T cells. The drugs are lowered to maintenance levels and are increased in case of rejection signs.

7. RECIPIENT T CELLS ANTIGENS PRESENTED BY ALLOGRAFT AND SELF APC Foreign MHC + any peptide Foreign MHC + self peptide Foreign MHC + any peptide Foreign MHC + foreign peptide Self MHC + foreign peptide Self MHC + foreign MHC-derived peptide MOLECULAR BASIS OF THE ALLO-RESPONSE HIGH PERCENTAGE OF RECIPIENT’S T CELLS ARE RESPONDING

8. Donor Graft APC Recipient T Recipient T Donor peptide Recipient peptide DIRECT PRESENTATION Recipient Host APC Recipient T Recipient T Donor peptide INDIRECT PRESENTATION PRESENTATION OF GRAFT - DERIVED PEPTIDES TO RECIPIENT’S T CELLS DEPLETION OF GRAFT – DERIVED PROFESSIONAL APC REDUCES REJECTION Host Versus Graft reaction HVG High percentage of T cells are activated

9. T cells are educated in the presence of self MHC allotypes, other allotypes are recognized as foreign. Rejection is caused by genetic differences between transplant donor and recipient. Rejection signs  Cell mediated, delayed type (hypersensitivity type IV) Highly polymorphic WBC antigens – HLA class I and II that are presenting peptides to T cells initiate an immune response with the potential to destroy the transplant. Crossmatch tests- to match HLA type between donor and recipient. Rejection of incompatible tissue is mediated primarily by lymphocytes but NK cells and antibody-mediated effector functions are also involved.

11. Hyper-acute rejection: Pre-existing antibodies against ABO or HLA antigens (previous pregnancy, transfusion, transplantation) Develops immediately ADCC, complement ABO incompatibility, Acute rejection: Effector T cells responding to HLA differences between donor ad recipient Direct pathway of allorecognition Takes days to develop Can be reduced or prevented using immunosuppression and T cell antibodies. CD8 and CD4 T cells respond to differences in HLA class I and II, respectively Chronic rejection: Months or years after transplantation Graft vasculature reactions, thickening  Ischmeia, loss of function Antibodies against HLA I and II classes, T cell mediated reaction (type IV)

12. * HYPERACUTE REJECTION * Xenograft or AB0 incompatible graft * Natural IgM antibodies against carbohydrates * Galα1-3Gal on xenograft endothelial cells * Antibodies generated upon previous blood transfusion, pregnancy or transplantation – MHC-specific antibodies bind to endothelial cells * Mismatch of recipient serum with donors B and T cells * Complement and clotting system * NK cell – mediated IgG-dependent ADCC * Necrotic tissue demage * EARLY ACUTE REACTION – 2 – 5 days * Previous sensitization of cytotoxic T cells * IgG-dependent ADCC * Necrotic tissue demage * LATE ACUTE and CHRONIC REACTION 7 – 21 days Causes failure of more than half the kidney and heart transplants after 10 years. * Th1 – mediated cellular immune response * Delayed Type Hypersensitivity * Fibrosis * Proliferation of smooth muscle cells * Atherosclerosis * Activation of cytotoxic T lymphocytes MECHANISMS OF TISSUE REJECTION

14. Acute rejection

15. Lymphocytes and plasma cells around renal tubules. Occurs after terminating immune suppression (CSA) ACUTE REJECTION T lymphocytes in The myocardium. Labeled with anti-CD3 antibody KIDNEY TRANSPLANTATION HEART TRANSPLANTATION REJECTION IS PRIMARILY MEDIATED BY MHC-SPECIFIC T LYMPHOCYTES BUT PLASMA CELLS ARE ALSO PRESENT Plasma cells T CELLS

18. Interstitial fibrosis and chronic inflammation. Renal arteries are fibrous and thickened. Chronic rejection Swallen rejected graft with haemorraegic and necrotic tissue area.

20. BONE MARROW TRANSPLANTATION

22. * Receipient’s immune response is inhibited * γ-irradiation, drugs * No rejection of the transplant * No host versus graft rejection * Donor bone marrow-derived mature T lymphocytes recognize recipient’s tissues * GVH- Graft versus host reaction - against all tissues * Acute autoimmun reaction, can be fatal * Elimination of mature T cells prevents GVH * Methotrexate and cyclosporin A inhibit GVHD * Elimination of mature T cells inhibits engraftment and anti-leukemia effect – may cause rejection BONE MARROW TRANSPLANTATION IS A SPECIAL CASE OF ORGAN TRANSPLANTATION Transplantation of the donor’s hematopoietic and immune systems to the recipient

23. * Degree of HLA matching of the healthy donor and the patient determines the benefits of transplantation! * Reduces alloreactions against the graft HVG  * Reduces graft versus host reaction GVH  * Ensures efficient presentation of graft antigens by graft APC in the thymus * Positive selection of graft T lymphocytes on host thymic epithelial cells will produce graft-derived T cells – shared MHC * The host’s immune system will be reconstituted by donor-derived lymphocytes DEFECTS OF HEMOTPOIETIC CELLS CAN BE CORRECTED BY BONE MARROW TRANSPLANTATION

24. - Liver - Pancreas - Pancreatic islet cells - Cornea - Kidney - Heart/Lung - Skin Survival and mismatching

25. Graft versus host reaction GVH Graft versus host disease – GVHD chronic and systemic Mature T cells transplanted with the bone marrow react with donor cells Elimination of donor T cells can prevent GVHD Elimination of donor T cells increases the occurence of graft rejection by donor T cells This is not a problem when bone marrow transplantation is used for correcting SCID BONE MARROW TRANSPLANTATION Special case of tissue transplantation Recipient APC Graft-donor T Graft-donor T Recipient peptide Graft Versus Host reaction

26. Join the organ donor register