The ultimate goal in organ transplantation is to establish a state of specific immunologic unresponsiveness to donor alloantigens. Currently we can effect only non-specific immunosuppression using drugs that are limited by confined efficacy, poor selectively and considerable toxicity. The Need for more specific immunosuppression, especially in the advent of xenotransplanation, mandates an aggressive approach to understanding mechanisms responsible for the induction and maintenance of immunologic tolerance. The overall goal of this proposal is to analyze in vivo molecular mechanisms responsible for induction and maintenance of tolerance to alloantigens. The hypothesis is that intracellular signals, mediated through the T cell receptor (TCR) complex, are altered in alloantigen tolerance.
Aim 1 is designed to develop an optimal strategy for obtaining alloantigen tolerance and to clarify the operative cellular mechanisms. Tolerance will be induced by intravenous infusion of allogeneic or semiallogeneic cells and the cellular events analyzed by measuring T cell function, cytokine secretion and phenotype.
Aim 2 will elucidate the associated TCR-mediated intracellular signaling events using state-of-the-art biochemical techniques. Analysis of intercellular signaling events is limited by the requirement for large numbers of clonally specific T cells. Therefore, this proposal takes advantage of mutant mice which express, transgenically, an alloantigen-specific TCR, 2C. The majority 9up to 95%) of T cells in the periphery of 2 c mice express the transgene and are thus specific for the naturally occurring peptide p2Ca and the class I alloantiggen (Ld). By providing a homogenous population of t cells expressing the tansgenic TCR of known allospecificity, this model allows analysis of the TCR-mediated biochemical signals operative in the in vivo alloresponse. The proposal is designed to allow the candidate to develop an independent research career related to a primary clinical interest in renal transplantation.
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