My long term objectives applicable to this grant proposal are to define and characterize the immune mechanisms involved in toxin induced interstitial nephritis, and to develop therapeutic modalities to prevent disease progression in this important cause of chronic renal disease. Although studies in experimental autoimmune interstitial nephritis have defined and clarified many aspects of immune mediated interstitial injury, different target antigens, effector cells, accessory molecules and cytokines may play a role in toxin induced interstitial injury. The focus of this proposal is to further characterize the immune response directed against heat shock proteins in chronic cadmium-induced interstitial nephritis. Preliminary evidence suggests that cytotoxic CD4+ TCRalpha/beta bearing T cells that are HSP65 reactive mediate cytotoxic injury in this model. I plan to further characterize the expression of HSP7O and HSP65 and relevant cytokines and accessory molecules in this model. The molecular aspects of T cell response to endogenous renal HSP will be analyzed by defining Vbeta gene use in disease inducing T cell clones. Functional characteristics of cytotoxic T cell clones will be defined including their cytotoxic capacities in vitro and their ability to produce inflammatory infiltrates in the whole animal model. Finally, I plan to examine nephritic kidneys to characterize HSP reactive T cells in kidneys with cadmium induced disease, and to culture and characterize T cell subsets defined in inflammatory infiltrates. Although it is beyond the scope of this current proposal, information gained from these studies will be used to develop strategies for treatment of toxin or stress induced interstitial nephritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK002259-01A1
Application #
2134095
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104