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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 firstname.lastname@example.org
Types of graft rejection - Hyperacute rejection very rapid (days) - Acute rejection 1 -2 weeks after transplant - Chronic rejection months - years after transplant
Hyperacute rejection is mediated by pre-existing antibodies against donor antigens
Acute rejection is based on development of an adaptive immune response
“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
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
Genetic mapping studies identified the MHC locus as a major determinant of successful transplantation
Allelic differences at loci other than MHC can also result in graft rejection
T cell alloresponse may be mediated by recognition of either alloMHC determinants, or peptides presented by the alloMHC
The Mixed-Lymphocyte Response (MLR) assay can be used to assess alloreactivity
Graft alloantigens can be recognized in two distinct ways: either directly presented by donor APCs, or indirectly, following processing and presentation on host APCs.
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
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
T cell activation requires a co-stimulatory signal in addition to the antigen receptor signal
CD28 can deliver a co-stimulatory signal following interaction with ligands of the B7 family
T cells become unresponsive to further stimulation if activated without a co-stimulatory signal
CTLA-4 Ig fusion protein can block co-stimulation and suppress immune responses
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
Restricting access to the graft Sphingosine analogue FTY720 inhibits lymphocyte recirculation and prolongs allograft survival
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
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.
Depletion of T cells from bone marrow prior to transplant reduces graft-versus-host disease
Sharing of at least one MHC allele is required for reconstitution of immune function following bone marrow transplantation