Interstitial nephritis continues to be an important form of renal pathology either as a primary process or as an essential component in the evolution of progressive renal failure from other causes. Accumulated evidence now credibly suggests that a variety of immunologic processes contribute to the overall pathogenesis of interstitial disease. These immunologic factors include the genetics of susceptibility, the loss of self-tolerance, the mechanism of disease activation and expression by antibody and T cells, and the protective influence of immunoregulation. The principle goal of this grant renewal is to extend our current understanding of such immunopathologic events using an experimental model of anti-tubular basement membrane disease producing interstitial nephritis in mice and rats. The substance of our effort will be to critically analyze the immunogenetic and interactional events surrounding T cell activation and effector cell differentiation, and with this understanding, to develop experimental strategies which can attenuate the expression of interstitial injury. These studies will carefully define the evolution of T cell communication, the role of associative-recognition and genetic restriction molecules, the character and interactional nature of soluble lymphokines secreted by antigen-activated cells, and the efficacy of investigator-induced suppressor T cell networks. Our investigations will take advantage of standard and recombinant rats and mice which differentially express disease, in vitro cell culture assays for effector T cell differentiation, affinity-purified inducer and regulatory lymphokines, delayed-hypersensitivity measurements of nephritogenic effector T cell function, T cell hybridomas producing soluble suppressor factors, and adoptive transfer protocols employing immuno-specific (antigen-reactive and idiotype-reactive) suppressor T cells. Collectively such studies should provide new and important information regarding the nephritogenic immune response mediating the development of interstitial renal lesions, and as such, should generate a logically constructed data base from which appropriate therapeutic interventions may be designed and employed using immunoregulatory probes.
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