Inflammatory interstitial nephritis, either as a primary or secondary condition, plays a critical role in the development of all forms of chronic renal failure. It is therefore important to understand those factors which underlie susceptibility to interstitial nephritis. The studies described in this grant proposal seek to both structurally and functionally define the basis for susceptibility to a T cell-mediated renal disease, the spontaneous nephritis of kdkd mice. This disease bears many similarities to inherited interstitial nephritis in humans. Previous studies have defined the antigenic and genetic specificity of the effector T cells mediating this lesion. A comparative analysis of the functional attributes of T cells from both kdkd (susceptible) and CBA/Ca (nonsusceptible) mice, revealed a unique abnormality in regulatory T cell function in kdkd mice which is critical for the expression of disease. This present analysis of determinants of susceptibility to autoimmune interstitial nephritis will proceed along three interrelated pathways. First, the purified target antigen of this disease, gp 56, will be used to generate both a monospecific, polyclonal antisera and oligonucleotide probes. These reagents will be used to identify and verify, through cDNA library screening, sequence analysis, and ultimately cDNA expression in a eukaryotic expression vector, the isolation of a cDNA encoding gp 56. Concomitantly I will develop a panel of effector and regulatory T cell clones from susceptible and nonsusceptible mice, and use them to compare T cell receptor variable region gene usage between susceptible and nonsusceptible mice. Important correlative studies will investigate recognition of target antigen-derived peptide sequences by effector and regulatory clones in order to explore functional correlates of epitope recognition. Significant bias in TcR gene usage and/or peptide recognition may provide a basis for specific immunosuppressive therapy. Lastly, the unique regulatory T cells from kdkd mice will be used to thoroughly characterize the cell-surface glycoprotein receptor for the Vicia Villosa lectin on these lymphocytes. This receptor is critical in the modulation of regulatory T cell function, which, in turn, is necessary for expression of disease. I believe these studies will provide novel information which will eventually redirect strategies to downregulate organ-specific immune responses and the natural history of immune-mediated interstitial nephritis.
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