Transplntation class


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Transplntation class

  1. 1. Transplant Immunology <ul><li>Rejection is an immune response that mediates injury and destruction of transplanted tissue </li></ul>
  2. 2. Types of Grafts • Autologous (self) e.g., BM, peripheral blood stem cells, skin, bone • Syngeneic (identical twin) • Allogeneic (another human except identical twin) • Xenogeneic (one species to another)
  3. 3. Figure 18.11
  4. 4. <ul><li>Rejection of tissues or organs that have been transplanted </li></ul><ul><li>Grafts perceived as foreign by the recipient undergo rejection </li></ul><ul><li>Graft rejection is a normal immune response against foreign major histocompatibility complex (MHC) proteins on the surface of graft cells </li></ul><ul><li>Likelihood of graft rejection depends on the degree to which the graft is foreign to the recipient </li></ul><ul><ul><li>Based on the type of graft </li></ul></ul>Graft Rejection
  5. 6. Transplant immunity “ Laws” of transplantation: Autogeneic grafts survive Syngeneic grafts survive Allogeneic grafts are rejected Parent-to-F1 grafts survive F1-to-parent grafts are rejected Xenogeneic grafts are rejected In an allogeneic graft, donor and recipient cells should have very similar types of surface antigens. So, why are allogeneic grafts always rejected?
  6. 8. Clinical Transplantation
  7. 9. These are averages. How well the donor and recipient are matched for MHC and minors has a big impact on graft survival. Tissue graft survival Most transplants require lifelong immunosupression with cyclosporin A or FK506. These drugs have many affects on the immune system but, overall, are not too toxic.
  8. 11. In addition to the MHC differences that usually distinguish one person from another, there are also many other genetic differences, Like MHC differences, these minor differences are manifest in proteins that can be recognized by the immune system and can be the targets of immune responses and graft rejection. Minor histocompatibility antigens can also cause graft rejection T cells usually mediate graft rejection
  9. 12. Minor histocompatibility antigens cause graft rejection after several weeks (3-8 weeks) Even a perfect MHC match between donor and recipient will result in graft rejection if there are minor-antigen differences
  10. 13. MHC a skin onto MHC a receipient  accept MHC a skin onto MHC b receipient  rejection MHC b skin onto MHC a receipient  rejection MHC b skin onto (MHC a XMHC b )F 1 receipient  accept (MHC a XMHC b )F 1 skin onto MHC b receipient  reject (MHC a XMHC b )F 1 skin onto (MHC a XMHC c )F 1 receipient  reject Any MHC the host “sees” as foreign will cause rejection Examples
  11. 14. Mechanisms of graft rejection
  12. 15. Preexisting antibodies against antigens in the graft (usually blood type antigen) can cause rapid graft rejection Hyperacute graft rejection mediated by antibodies
  13. 16. A fetus is an allograft that may induce an immune response in the mother but is usually protected from the mother’s immune system.
  14. 17. <ul><li>Sites at which grafts are not likely to be rejected </li></ul><ul><li>Different sites are privileged for different reasons </li></ul><ul><ul><li>The brain lacks lymphatic vessels, and its blood vessel walls are impermeable to lymphocytes such as T cells </li></ul></ul><ul><ul><li>Cornea lacks extensive blood vessels </li></ul></ul><ul><ul><li>Eyes and testes contain naturally high levels of immunosuppressive molecules </li></ul></ul><ul><ul><li>Other sites either lack dendritic cells or express low levels of MHC molecules, so antigen processing does not occur </li></ul></ul>Privileged Sites
  15. 18. <ul><li>The fetus is not a privileged site but is not rejected </li></ul><ul><li>Rejection is prevented by the many different immunosuppressive mechanisms </li></ul><ul><ul><li>Early embryos do not express MHC class I and II molecules on the placental layer that is in contact with maternal tissues </li></ul></ul><ul><ul><li>Cytokines that enhance MHC expression have no effect on placental cells </li></ul></ul><ul><ul><li>T cells are prevented from functioning in the placenta to reject the fetus </li></ul></ul>Why Fetuses are Not Rejected
  16. 19. Tempo of rejection reactions
  17. 20. <ul><li>Rapid: occurs in minutes to days </li></ul><ul><li>Mediated by preformed antibodies and complement </li></ul><ul><li>No treatment </li></ul><ul><li>Prevention </li></ul>Hyperacute Rejection
  18. 21. Hyperacute reaction due to preformed antibodies
  19. 22. Hyperacute rejection Within minutes of transplantation Results from recipient’s pre-existing, circulating Ab Ab binds donor Ag in transplanted tissue blood vessels Clotting and complement mechanisms activated Death of transplanted tissue due to lack of oxygen
  20. 25. <ul><li>Most common </li></ul><ul><li>Occurs days to months post-transplant </li></ul><ul><li>Cell-mediated immune response </li></ul><ul><li>Treated by increasing the net state of immunosuppression </li></ul>Acute Rejection
  21. 27. <ul><li>Progressive decline in allograft function </li></ul><ul><li>Presents differently in each organ transplant type </li></ul><ul><li>Occurs months to years post-transplant </li></ul><ul><li>Therapy: prevent vs. delay the inevitable? </li></ul>Chronic Rejection
  22. 30. <ul><li>MHC compatibility between donor and recipient can be hard to achieve due to a high degree of variability among individuals </li></ul><ul><ul><li>The more closely the donor and recipient are related, the smaller the difference in their MHC </li></ul></ul><ul><ul><li>Usually preferable that grafts are donated by a parent or sibling possessing MHC antigens similar to those of the recipient </li></ul></ul>Donor-Recipient Matching and Tissue Typing
  23. 31. <ul><li>Tissue typing used to match donor and recipient as closely as possible when a closely related donors is not available </li></ul><ul><ul><li>Individual whose MHC proteins most closely match those of the donor is chosen to receive the graft </li></ul></ul><ul><ul><li>A match of 50% or less of the MHC proteins is usually acceptable for most organs, but near absolute matches are required for successful bone marrow transplants </li></ul></ul>Donor-Recipient Matching and Tissue Typing
  24. 32. MHC Typing methods <ul><li>Serological (antisera) </li></ul><ul><ul><li>Lymphocyte immunization </li></ul></ul><ul><ul><li>Skin grafts </li></ul></ul><ul><ul><li>Pregnancy sera </li></ul></ul><ul><ul><li>Monoclonal antibodies </li></ul></ul><ul><ul><li>Erythrocytes typing (birds) </li></ul></ul><ul><li>Cellular assays </li></ul><ul><ul><li>Microcytotoxicity (antibody) </li></ul></ul><ul><ul><li>Mixed leucocyte response (MLR) </li></ul></ul><ul><ul><li>Cell-mediated lympholysis (CML) </li></ul></ul><ul><li>DNA typing </li></ul>
  25. 33. Tissue typing
  26. 34. Identification of HLA expressed by donor and recipient
  27. 36. Cross-matching
  28. 37. IMPROVEMENT IN GRAFT SURVIVAL <ul><li>Transplantation within families </li></ul><ul><li>ABO typing eg. for kidney grafts </li></ul><ul><li>Tissue typing </li></ul><ul><li>Cross-matching </li></ul><ul><li>Immunosuppression </li></ul>
  29. 38. <ul><li>Valuable for successful transplants and for treating autoimmune disease </li></ul><ul><li>Classes of immunosuppressive drugs </li></ul><ul><ul><li>Corticosteroids </li></ul></ul><ul><ul><li>Cytotoxic drugs </li></ul></ul><ul><ul><li>Immunophilins </li></ul></ul><ul><ul><li>Lymphocyte-depleting therapies </li></ul></ul>Immunosuppressive Drugs
  30. 39. The Four Classes of Immunosuppressive Drugs Table 18.4
  31. 41. Immunosuppressive Strategies <ul><li>Combination therapy </li></ul><ul><li>Induction therapy </li></ul><ul><li>Maintenance therapy </li></ul><ul><li>Anti-rejection therapy </li></ul>
  32. 42. Immunosuppressive Strategies <ul><li>Combination therapy with multiple-drug regimens </li></ul><ul><ul><li>Rationale: </li></ul></ul><ul><ul><ul><li>Maximize immunosuppression </li></ul></ul></ul><ul><ul><ul><li>Minimize adverse effects </li></ul></ul></ul><ul><ul><ul><li>Provides flexibility for adjustment </li></ul></ul></ul>
  33. 43. <ul><li>Induction Therapy: </li></ul><ul><ul><li>Goals: </li></ul></ul><ul><ul><ul><li>Decrease incidence of acute rejection </li></ul></ul></ul><ul><ul><ul><li>Allows for minimization of maintenance agents in the early postoperative period </li></ul></ul></ul>Immunosuppressive Strategies
  34. 44. Induction Therapy <ul><li>Maintenance </li></ul><ul><li>Immunosuppression </li></ul><ul><li>Regimen </li></ul><ul><li>Induction </li></ul><ul><li>Agent </li></ul>+
  35. 45. Induction Agents <ul><li>Anti-T-Cell Antibodies </li></ul><ul><ul><li>Thymoglobulin ® </li></ul></ul><ul><ul><li>Muromonab OKT3 ® </li></ul></ul><ul><li>IL-2 Receptor Antagonists </li></ul><ul><ul><li>Daclizumab </li></ul></ul><ul><ul><li>Basiliximab </li></ul></ul>
  36. 46. Maintenance Immunosuppression <ul><li>Calcineurin Inhibitors </li></ul><ul><ul><li>Cyclosporine </li></ul></ul><ul><ul><ul><li>CyA, Neoral ® , Gengraf ® , Sandimmune ® </li></ul></ul></ul><ul><ul><li>Tacrolimus </li></ul></ul><ul><ul><ul><li>FK506/FK/Prograf ® </li></ul></ul></ul>
  37. 47. Maintenance Immunosuppression <ul><li>Adjunctive agents </li></ul><ul><ul><li>Antiproliferative agent </li></ul></ul><ul><ul><ul><li>Mycophenolate mofetil (Cellcept ®) </li></ul></ul></ul><ul><ul><ul><li>Azathioprine (Imuran ® ) </li></ul></ul></ul><ul><ul><li>mTOR Inhibitors </li></ul></ul><ul><ul><ul><li>Sirolimus </li></ul></ul></ul><ul><ul><ul><ul><li>Rapamycin/Rapamune ® </li></ul></ul></ul></ul>
  38. 48. Maintenance Immunosuppression <ul><li>Corticosteroids </li></ul><ul><ul><li>Prednisone </li></ul></ul>
  39. 49. Summary: Immunosuppressive Plan <ul><li>Calcineurin inhibitor </li></ul><ul><ul><li>Cyclosporine </li></ul></ul><ul><ul><li>tacrolimus </li></ul></ul><ul><li>Adjunctive agent </li></ul><ul><ul><li>Mycophenolate </li></ul></ul><ul><ul><li>rapamycin </li></ul></ul><ul><li>Steroid </li></ul><ul><ul><li>prednisone </li></ul></ul><ul><li>Daclizumab </li></ul><ul><li>or </li></ul><ul><li>OKT3 </li></ul><ul><li>or </li></ul><ul><li>Thymoglobulin </li></ul>+