PATHOPHYSIOLOGY OF CRYOGLOBULNEMIC GLOMERULONEPHRITIS

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DESCRIPTION (provided by applicant): Hepatitis C (HCV) is the most common blood-borne infection in the United States and is endemic in most areas of the world. We and others have previously shown that in humans, the principal renal manifestation of chronic hepatitis C infection is development of a membranoproliferative glomerulonephritis (MPGN) most often associated with cryoglobulinemia. Cryoglobulins are immunoglobulin proteins that reversibly precipitate in the cold, leading to systemic disease in humans. Overexpression of thymic stromal lymphopoietin (TSLP), a recently cloned cytokine that promotes B cell development, in transgenic mice leads to production of large amounts of circulating mixed cryoglobulins and a renal disease that closely resembles human MPGN. In this proposal, we seek support for studies that will define the role of the immunoglobulin binding Fc receptors (FcR) of leukocytes, major mediators of inflammation in immune complex deposition disease, in this model and the role of the PDGF family of growth factors that mediates glomerular mesangial cell proliferation. Having developed a reproducible model of cryoglobulinemia/MPGN, we seek to develop a major modification of the model in Specific Aim 1 that will allow better testing of therapeutic applications in glomerulonephritis by allowing us to regulate the exposure of the kidney to the initiating cryoglobulinemic stimulus. We will place the promoter regulating expression of the TSLP gene under the control of a tetracycline responsive regulatory element using recently established technologies. Specific Aim 2 will address the hypothesis that activation of specific classes of leukocyte Fc receptors are required for the full development of MPGN. The functional role of Fc receptors will be tested using combined transgenic and knockout mice. Inbreeding of multiple Fc receptor deficient strains with TSLP mice will shed light on the role of inflammatory pathways mediated by these two receptors in this model. We will test specific therapeutic interventions (e.g., neutralizing antibodies for these receptors) to interrupt these inflammatory pathways for efficacy in treating glomerular injury. In Specific Aim 3 we will test the efficacy of blocking the activity of the PDGF growth factor family in ameliorating disease. Specific Aim 4 will examine the effects of these interventions on systemic cryoglobulinemia. It is anticipated that the findings will lead to better treatments for cryoglobulinemia and associated MPGN.