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Targeting complement inhibitors to the human proximal tubule

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Nearly all glomerular diseases are accompanied by tubulointerstitial (Tl) pathology that is inextricably linked to outcome. Such Tl injury may occur because the abnormal glomerular ultrafiltrate contains potentially injurious proteins, including those of the spontaneously active complement system. Although most host cells bear complement regulatory proteins (CRPs), these are not well expressed by proximal tubular epithelial cells (PTECs). There are strong data supporting that deleterious C5b-9 activation occurs on PTECs in proteinuric conditions. We have used exogenous CRPs to limit complement activation on cells and in tissues, including in renal disease models, and have recently used recombinant monoclonal antibodies (mAbs) and C3-binding complement receptors (CR2) to selectively target CRPs to relevant cells undergoing complement attack, including the rat PTEC in proteinuria-induced Tl injury. The research proposed here will apply this approach to target the specific C5b-9 inhibitor, CD59, to the human PTEC. The first aim will be to study a human PTEC culture that retains native characteristics, including expression of antigens that can be targeted, the repertoire of CRPs, and the functional response to C5b-9. Complement activation as is likely to occur upon exposure to recently filtered plasma proteins will be modeled on these cells, and the phenotypic response determined, including parallels to what occurs over time in progressive renal disease. We will then evaluate PTEC antigens that can be used for targeted therapy. Candidate antigens will be studied, including those with human homologues from our recent studies in the rat, and those upregulated in human PTEC injury. In addition, the potential of using CR2 to target sites of complement activation on the PTEC will be evaluated. Once we have created a model system and identified viable targets to deliver CRPs, we will create mAb/CR2-CD59 chimers to target human PTECs. The work proposed here applies fundamental principles and research derived from experimental models of proteinuria-induced Tl injury to develop therapy for the analogous human diseases. Kidney disease has reached epidemic proportions, costing us in lives and money. The work proposed here uses modern technology to design treatment for these disorders. Although these are considered pilot and high-risk studies, successful completion could give us treatments for immediate use in clinical studies.

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