The goal of this project is to test critically the hypothesis that the erythrocyte complement receptor (E-CR) system provides protection against the development of immune complex (IC)-mediated glomerulonephritis (GN). There is considerable evidence that the E-CR system, which is unique to the primate, should be protected by providing an IC clearing mechanism and an IC processing mechanism. However, that evidence is based entirely on extrapolation for in vitro and acute in vivo studies of IC/E-CR interactions, and clinical observations. That is, there has been no critical test of the role of the E-CR system under conditions of an actual IC-mediated disease. Our current NIH grant was provided specifically to develop a model of IC-mediated disease in the nonhuman primate that could be used to test critically the role of the E-CR system. As described herein, that work has been successful. Thus, it is now feasible to undertake a critical testing of the role of the E- CR system in IC-mediated disease in the primate. We propose the following critical test the E-CR system in IC-mediated disease: The evolution of experimentally induced IC-mediated GN will be assessed in two groups of primates by morphometric analysis of serial renal biopsies and detailed clinical studies. The two groups will be comparable initially in all relevant parameters, however, in one group (H-Group) the progressive fall in E-CR levels that develops in active IC-mediated disease will be prevented by twice weekly erythrocyte exchange transfusions using compatible donors with high E-CR levels. In the other group (L-Group) the fall in E-CR levels that develops in active IC-mediated disease will be prevented by twice weekly erythrocyte exchange transfusions using compatible donors with high E-CR levels. In the other group (L-Group) the fall in E-CR levels will be exaggerated by twice weekly erythrocyte exchange transfusion using compatible donors with low E-CR levels. Cynomolgus monkeys (CM) were used for the development of the model and will be used for the proposed studies because some CM have E-CR levels similar to that of man (200-1200 CR/E), while other CM have lower (<100) or higher (>2,000) CR/E than man. Thus, within the CM species, primates can be selected for GN induction that are similar to man with respect to E-CR levels, and primates can be selected to serve as erythrocyte donors to either raise or lower the mean CR/E in the CM undergoing GN induction. Pilot studies have demonstrated that all aspects of the study described above are feasible and, if the E-CR system exerts an important protective effect, the study as designed has sufficient statistical power to identify those differences. Two additional phenomena will be investigated concurrently in the CM subjected to the GN Induction Protocol: 1) Do diagnostic changes in E-CR number, distribution, or function occur that can predict the onset of GN? 2) Is specific antibody synthesis rate affected by E-CR level as might be expected if IC processing by E-CR is an important immunoregulatory event, as some studies suggest? The proposed studies should shed new light on the pathogenesis of IC-mediated disease in the primate and could suggest new diagnostic and therapeutic approaches to IC-mediated disease in man.
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