Our research focuses on development of a novel and potentially general therapeutic designed to remove autoantibodies from the circulation. It is now established that C3b-opsonized immune complexes bound to the primate red cell complement receptor (CR1) are cleared from the circulation and transferred to fixed tissue macrophages of the reticuloendothelial system (RBS). Previously we adapted this red cell-mediated binding and transfer reaction to facilitate clearance of circulating antigens to the liver and spleen in monkeys through use of cross-linked monoclonal antibodies specific for CR1 and the target antigens. We have now prepared antigen based heteropolymers (AHP) consisting of a monoclonal antibody to red cell CR1 which is cross-linked with a specific autoantigen, such as dsDNA, or the acetylcholine receptor (AChR). We are using these AHP in the presence of non-human primate and human red cells to bind quantitatively anti-dsDNA autoantibodies from SLE sera. We are performing similar studies with prototype autoantibodies: mouse mAbs specific for dsDNA and the AChR, respectively. We have conducted successful in vivo preliminary studies in which passively transferred human anti-dsDNA antibodies and the prototype autoantibodies were removed from the circulation of monkeys via the AHP- red cell system. In the case of the AHP/anti-AChR mAb system, our dynamic imaging experiments confirmed that the cleared prototype autoantibody deposited in the liver and spleen where it was phagocytosed and degraded. Specific AHP-mediated binding of these autoantibodies to red cells occurs equally well in the presence or absence of complement and in no instances were the red cells lysed, or cleared from the circulation (in vivo experiments). We plan to extend these findings in order to determine the potential feasibility of the AHP approach. We will examine in detail the quantitative and qualitative aspects of autoantibody binding to specific AHP under in vitro and in vivo conditions. A variety of RIAs are used to follow binding and clearance of target autoantibodies. We will continue to conduct dynamic imaging experiments with an Anger camera which allow us to identify the organs which take up the cleared material. We will also attempt to establish an in vitro model for the transfer reaction in order to investigate the mechanism by which immune complexes or AHP-autoantibody complexes are removed from primate red cell CR1 and transferred to fixed tissue macrophages of the RES.
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