Introduce transplants to allow normal functions

1. TISSUE TRANSPLANTATION Replacement of diseased, demaged or worn-out tissues REQUIREMENTS • Introduce transplants to allow normal functions • Maintain the health of both the recipient and the transplant • The immune system of the recipient must be prevented to mount an adaptive immune respone against the graft to avoid rejection •  inactivation of the immune system

2. ORGAN, TISSUE OR CELL TRANSPLANT ALLOGENEIC SYNGENIC allograft Kidney, cornea, liver, heart, lung bone marrow-derived haematopoietic cells (HSC) AUTOLOGOUS isograft autograft Skin, muscle, stem cell, dendritic cell, cartilage BLOOD TRANSFUSION bone marrow-derived haematopoietic cells (HSC)

3. BLOOD GROUP AND HLA-SPECIFIC ANTIBODIES INDUCE HYPERACUTE REJECTION THROUGH COMPLEMENT ACTIVATION • THE TRANSFUSION REACTION IS MEDIATED BY ANTIBODIES • Red blood cells do not express MHC class I or class II molecules • A, B, 0 antigens are expressed by endothelial cells of blood vessels (solid vascularized organs) • Antibodies to blood group antigens bind to blood vessels, activate complement • Type III hypersensitivity • Hyperacute rejection – cannot be reversed, should be avoided • Anti – HLA antibodies • arise from pregnancy, blood transfusion, previous transplant • Cross match: test recipient’ serum to donor lymphocytes • Panel reactive antibody (PRA) – % of positive reactions • C-activation • Flow cytometry – more sensitive • Separated T and B cells to detect MHC class I and MHC class II specific antibodies • Anti – MHC I react with both B and T lymphocytes • Anti – MHC II react with B lymphocytes only

4. GRAFT REJECTION IS THE RESULT OF SPECIFIC IMMUNE RESPONSE Primary rejection mouse strain 10 days 6 months Lymfocyte transfer from immunized mouse Secondary rejection mouse strain 3 days - MEMORY Naive mouse Primary rejection mouse strain 10 days Rapid rejection of the transplant is mediated by a memory immune response

5. ORGAN, TISSUE OR CELL TRANSPLANTATION ALLOGENEIC Transplant rejection Host versus graft HVG

6. TRANSPLANTATION IMMUNOLOGY • THE ALLO-REACTIVE IMMUNE RESPONSE IS DIRECTED AGAINST TRANSPLANTATION ANTIGENS • Major transplantation antigens are encoded by classical MHC genes • Minor transplantation antigens are encoded by any polymorphic gene and are recognized as peptides in the context of MHC • Blood group antigens are considered as tissue-specific transplantation antigens • T CELLS ARE EDUCATED IN THE PRESENCE OF SELF MHC ALLOTYPES • OTHER MHC ALLOTYPES ARE RECOGNIZED AS FOREIGN BY T LYMPHOCYTES • REJECTION OF INCOMPATIBLE TISSUE IS MEDIATED PRIMARILY BY T LYMPHOCYTES • NK CELLS AND ANTIBODY MEDIATED EFFECTOR FUNCTIONS ARE ALSO INVOLVED

7. PRESENTATION OF GRAFT - DERIVED PEPTIDES TO RECIPIENT’S T CELLS Recipient T Recipient T Recipient peptide Donor peptide DonorGraft APC Recipient Host APC Recipient T Recipient T Donor peptide Donor peptide DIRECT PRESENTATION INDIRECT PRESENTATION Demaged, apoptotic/necrotic tissue cells and soluble proteins (MHC) Host Versus Graft reaction HVG High percentage of T cells are activated DEPLETION OF GRAFT – DERIVED PROFESSIONAL APC REDUCES REJECTION

8. MOLECULAR BASIS OF THE ALLO-RESPONSE ANTIGENS PRESENTED BY ALLO- AND SELF APC RECIPIENT T CELLS Allo-MHC + allo-peptide Allo-MHC + allo-peptide Allo-MHC + self-peptide Allo-MHC + self peptide Allo-MHC + any-peptide Allo-MHC + any-peptide Self-MHC + allo-peptide Self-MHC + allo-peptide Self-MHC+any-peptide HIGH PERCENTAGE OF RECIPIENT’S T CELLS ARE RESPONDING

9. MECHANISMS OF TISSUE REJECTION • 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 • Th1 – mediated cellular immune response • Delayed Type Hypersensitivity • Fibrosis • Proliferation of smooth muscle cells • Atherosclerosis • Activation of cytotoxic T lymphocytes

10. ACUTE REJECTION KIDNEY TRANSPLANTATION HEART TRANSPLANTATION T CELLS Plasma cells REJECTION IS PRIMARILY MEDIATED BY MHC-SPECIFIC T LYMPHOCYTES BUT PLASMA CELLS ARE ALSO PRESENT

11. Chronic rejection

12. ORGAN, TISSUE OR CELL TRANSPLANTATION Pre-treatment Bone marrow ALLOGENEIC Treat tumor Correct deficiency Cardiovascular diseases Graft versus Host GVH GVHD Transplant rejection Host versus graft HVG

13. BONE MARROW TRANSPLANTATION IS A SPECIAL CASE OF ORGAN TRANSPLANTATION Transplantation of the donor’s hematopoietic and immune systems to the recipient • 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 • 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

14. CYCLOSPORIN (CSA) AND TACROLIMUS (FK506) INAKTIV ACTIVE Dephosphorylation NF-AT translocation to the nucleus Blocked by CSA and FK506 Gene activation, expression of cytokines and activation molecules

15. DEFECTS OF HEMOTPOIETIC CELLS CAN BE CORRECTED BY BONE MARROW TRANSPLANTATION • 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

16. BONE MARROW TRANSPLANTATION Special case of tissue transplantation • 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 Graft-donor T Recipient peptide Recipient APC survive Graft-donor T Recipientpeptide Graft Versus Host Reaction

17. TISSUE DEMAGE OF THE SKIN IN GVHD

18. X-SCID child – Bubble Baby Sterile environment No increased frequency of tumors Sensitivity to infections Therapy by bone marrow transplantation Gene therapy 2000