To evaluate the consequences of allosensitization in transplant recipients, the inter-relationships between cellular allosensitization, humoral allosensitization, and acute graft rejection must first be defined.
Specific Aim 1 will identify the pathways of T cell sensitization that lead to allo-reactive DTH in allograft recipients. CD4plus and CD8 plus T cells from graft allosensitized normal, IFNgammaKO or IL4KO mice will be tested for their ability to mediate DTH after alloantigen presentation via autologous vs allogeneic APC. These studies are designed to test the hypothesis that allograft-induced DTH is mediated by IFNgamma but not IL4-producing CD4plus or CD8plus T cells after stimulation with donor alloantigen by either syngeneic or allogeneic APC.
Specific Aim 2 will identify the pathways of T cell sensitization that lead to donor-reactive IgG production in allograft recipients. CD4plus of CD8plus T celts from graft allosensitized normal, IFNgammaKO or IL4KO mice will be tested for the ability to promote donor-reactive IgG production when transferred into syngeneic B-SCID mice. These studies are designed to test the hypothesis that graft-induced IgG is promoted by IFNgamma or IL4 producing CD4plus T cells after stimulation with donor alloantigens via syngeneic, but not allogeneic APC.
Specific Aim 3 will determine the patterns of allosensitization which distinguish acute rejection, transplantation tolerance and chronic rejection. Alloractive DTH and alloantibody responses in cardiac allograft recipients made tolerant by immunosuppression will be evaluated. These studies are designed to test 2 hypotheses: 1) that cellular and humoral sensitization are dissociated in tolerant allograft recipients, and 2) that DTH is indicative of cellular sensitization leading to acute allograft rejection, while alloantibodies are indicative of humoral sensitization leading to chronic rejection.
Specific Aim 4 will develop methods to evaluate cellular and humoral allosensitization patterns in human transplant patients. ELISA and a novel trans vivo DTH analyses to monitor human antibody and DTH responses to TT or alloantigens will also continued to be developed, evaluated, and field tested using sera and PBMC from allosensitized and non-sensitized transplant patients. These techniques could be used to monitor patterns of allosensitization in transplant patients, with the goal of identifying patterns of allosensitization indicative of risk for post-transplant immunologic complications (acute or chronic rejection).
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