Achieving long-term allograft survival in the absence of ongoing immunosuppressive treatment is an important goal in clinical organ transplantation. Homeostatic mechanisms that regulate T-lymphocyte survival during alloimmune responses are probably central to determining the fate of a transplanted organ. There is evidence to show that T-lymphocytes are susceptible to activation-induced apoptotic death following exposure to high antigen dose or persistent antigenic stimulation. The extent to which activation-induced T-cell death contributes to long-term allograft survival and transplantation tolerance is not known. The underlying thesis in this proposal is that activation-induced death of alloreactive T-cells is necessary but not sufficient for induction of long-term allograft survival and transplantation tolerance; suppression of factors that rescue T-cells from death is required to achieve these outcomes.
Specific aim 1 is to study the role of activation-induced T-cell death in the induction of long-term allograft survival and transplantation tolerance to vascularized allografts. Heart transplant acceptance will be examined in gene-knockout mice deficient in membrane molecules or cytokines that mediate activation-induced cell death. Biochemical, histochemical, and flow cytometric techniques will be used to study apoptosis of alloreactive T-cells in vivo and in vitro.
Specific aim 2 is to study the role of activated antigen presenting cells in rescuing T-lymphocytes from cell death, thus precluding long term-allograft survival and transplantation tolerance. In vivo and in vitro systems will be used to determine which antigen presenting cell cytokines or membrane molecules can rescue activated, alloreactive T-lymphocytes from apoptosis. An in vivo system consisting of scid mice transfused with T-cell receptor-transgenic lymphocytes will be utilized to study intragraft factors that prevent activation-induced T-cell death. The proposed studies will enhance our understanding of T-cell survival following allostimulation and refine our abilities to design and implement new therapies that induce tolerance to transplanted organs.
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