NEPHROTOXIC NEPHRITIS IN CCR5 AND CXCR3 KNOCKOUT MICE

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Glomerular inflammation, crescent formation and interstitial fibrosis, the major features of severe glomerulonephritis (GN), are mediated by the infiltration of leukocytes. This infiltrate results from the coordinated release of a number of chemotatic. Recently much attention has focused on the role of chemokines in this disease. Studies in humans have shown up-regulation of several chemokines (RANTES, MIP-1beta, MCP-1) and chemokine receptors (CCR5, CXCR3) in renal glomeruli and interstitium but their functional role remains largely undefined. Similarly, studies in animal models of inflammatory GN have shown up-regulation of several chemokines and chemokine receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, receptors at different stages of the disease. In particular, the chemokines, MIP1-beta, MCP-1, RANTES, MIP-2, eotaxin, IP10, and lymphotactin (fractalkine), and the chemokine receptors. CCR1, CCR2, CCR5, and CXCR3 are highly expressed in models of crescentic GN. In addition, chemokines and their receptors influence the balance between the Th1 and Th2 helper T cell subsets. This in turn may alter the severity of experimental crescentic GN, which results from a predominantly TH1 response. We hypothesize in this proposal that disrupting CCR5 or CXCR3 will affect the development of glomerular crescents and post-inflammatory interstitial fibrosis in a murine model of crescentic GN and alter the balance between Th1 and Th2 in the response to exogenous antigen. We plan to test this hypothesis in an accelerated model of murine nephrotoxic nephritis using mice deficient in either CCR5 or CXCR3 as compared to an accelerated model of murine nephrotoxic nephritis using mice deficient in either CCR5 or CXCR3 as compared to wild type controls. Studying the effects of disrupting these two chemokine receptors and their ligands on the wild type controls. Studying the effects of disrupting these two chemokine receptors and their ligands on the development and progression of GN and the initiating immune response will have important implications for the design of therapies to neutralize these potent inflammatory mediators in glomerular and other autoimmune diseases.