The overall goal of transplantation research is the development of clinically applicable strategies that are capable of inducing long-term tolerance of transplanted organs. Previous studies have shown that HSPs Hsp70, Hsp90, and gp96 isolated from tumor tissue can induce tumor-specific immunity and that this response is induced by tumor- specific peptides associated with the heat shock proteins. In contrast, high doses of gp96 lead to the generation of regulatory T cells with the capacity to down-regulate immunity in a tumor-peptide specific manner. This study will test the hypothesis that HSPs purified from donor tissue carry a MHC alloantigenic fingerprint of the donor and that the therapeutic administration of high doses of gp96 purified from donor tissue to recipients can down- regulate anti-donor reactivity and induce long-term allograft survival. Gp96 will be purified from PVG rat donors and administered to DA (low responder) and Wistar Furth (high responder) rat recipients of PVG cardiac allografts. The effects of gp96 on cardiac graft survival will be monitored. The mechanisms by which regulation are achieved will be evaluated by determining the effects of gp96 treatment on the proliferative and cytokine secretion phenotype of alloreactive cells isolated from recipient animals. The capacity of cells from gp96-treated animals to regulate allograft immunity after adoptive transfer into untreated animals will also be determined. The demonstration that donor-derived gp96 can specifically down-regulate the induction of allograft immunity may revolutionize organ transplantation. In particular, gp96 would present the alloantigenic fingerprint of the donor to the recipient immune system, and the requirement for tissue cross-matching may be rendered unnecessary.
