Throughout his clinical fellowship in pediatric nephrology and his postdoctoral training in immunology the candidate's interests have been focused on the relationship of complement and host immune response. This proposal represents an excellent opportunity for the candidate to work in a well regarded research environment which will contribute immensely to the candidate's knowledge of complement biology as well as immunologic aspects of renal injury. This proposal is based on two distinct, but interrelated findings; first, that the receptors for the anaphylatoxins, C3a and C5a, are highly expressed in proximal tubular epithelium, and second thatC3a and C5a have the capacity to attenuate CD4+ Thl T-cell responses. Based on the hypothesis that C3a and C5a, acting directly on proximal tubular epithelial cells and on the adaptive immune response, promote renal injury, we propose to define the role of C3a and C5a in the murine 2-Bromoethylamine (BEA) nephritis model. Initially, we will characterize both the expression and function of the C3a and C5a receptors in primary murine proximal tubular epithelial cells. Second, immunologic responses with respect to antigen presenting cell and T-cell function, as well as T-cell dependent B-cell activation will be defined in C3a and C5a receptor deficient mice. Lastly, functional and histological differences between C3a and C5a receptor deficient mice and wildtype littermate controls will be defined in both the acute tubular necrosis phase and the chronic tubulointerstitial disease phase of BEA induced nephritis. In addition, mononuclear cells will be isolated from renal tissue, phenotyped, and functionally characterized by patterns of cytokine production both at the protein and mRNA levels. The candidate's and the sponsor's interests are in understanding the role of the anaphylatoxins in immune mediated pathogenesis. The efforts of the proposal will have direct application to human disease. At the completion of this Award, the candidate will be prepared to continue as a highly productive independent investigator in the area of renal immunopathogenesis
