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Transplantation David Straus
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  1. Transplantation David Straus Reading: Immunobiology Janeway, et al. Chpt 13: 13-16 to 13-24, 13-26, 13-29 Chpt 14: 14–1 to 14-4, 14-7

  2. Types of graft rejection - Hyperacute rejection very rapid (days) - Acute rejection 1 -2 weeks after transplant - Chronic rejection months - years after transplant

  3. Hyperacute rejection is mediated by pre-existing antibodies against donor antigens

  4. Acute rejection is based on development of an adaptive immune response

  5. Skin graft studies implicate the adaptive immune response in rejection

  6. “Chronic” rejection is typified by graft vascular disease resulting from inflammatory injury Heart transplant, chronic rejection. Concentric fibrosis of an artery with the later stages of graft vascular disease

  7. Allogeneic response to grafts - Largely dependent on differences between donor and host MHC - But, other allelic differences also contribute to the alloresponse - alloantigens may be presented by donor or host APCs

  8. Genetic mapping studies identified the MHC locus as a major determinant of successful transplantation

  9. Allelic differences at loci other than MHC can also result in graft rejection

  10. T cell alloresponse may be mediated by recognition of either alloMHC determinants, or peptides presented by the alloMHC

  11. The Mixed-Lymphocyte Response (MLR) assay can be used to assess alloreactivity

  12. Graft alloantigens can be recognized in two distinct ways: either directly presented by donor APCs, or indirectly, following processing and presentation on host APCs.

  13. Activation of alloreactive T cells mediates acute graft rejection

  14. Several non-specific immunosuppressants can be used in transplantation Steroids are anti-inflammatory but act on a large number of tissues Cytotoxic drugs block DNA synthesis and target dividing cells

  15. Calcineurin phosphatase controls NFAT activity

  16. Cyclosporin A and tacrolimus block T cell activation by inhibiting NFAT function CsA and tacrolimus bind target proteins in the cytosol The drug- protein complex associates with calcineurin preventing the dephosphorylation of NFAT NFAT is unable to translocate into the nucleus to activate IL-2 gene expression

  17. T cell activation requires a co-stimulatory signal in addition to the antigen receptor signal

  18. CD28 can deliver a co-stimulatory signal following interaction with ligands of the B7 family

  19. T cells become unresponsive to further stimulation if activated without a co-stimulatory signal

  20. CTLA-4 Ig fusion protein can block co-stimulation and suppress immune responses

  21. T cells can also be tolerized by modifying the TCR signal Anti-CD4 antibody provided at the time of engraftment can lead to the induction of tolerance

  22. Restricting access to the graft Sphingosine analogue FTY720 inhibits lymphocyte recirculation and prolongs allograft survival

  23. Fetus as a tolerated allograft Immune privileged site Restricted access Immunosuppression - Placental indoleamine dioxygenase (IDO) reduces tryptophan levels and represses T cells - secretion of TGFß, IL-4, IL-10 suppresses Th1 responses

  24. Graft-versus-Host Disease is associated with bone marrow transplants 1. Pretreatment to ablate host immune system, or reduce malignancy, causes tissue damage. 2. APCs recognize damage and activate allo-responsive donor T cells. 3. Activated T cells and other immune cells induce tissue damage.

  25. Depletion of T cells from bone marrow prior to transplant reduces graft-versus-host disease

  26. Sharing of at least one MHC allele is required for reconstitution of immune function following bone marrow transplantation