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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK030280-05
Application #
3229353
Study Section
Pathology A Study Section (PTHA)
Project Start
1982-06-01
Project End
1990-05-31
Budget Start
1986-06-01
Budget End
1987-05-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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