Complement and Platelets in Antibody-Medicated Rejection

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New diagnostic tools and heightened clinical awareness have increased the recognition of antibodymediated rejecfion (AMR). However, the pathogenesis of AMR is incompletely understood, and not all of the mediators of AMR have been defined. After a review of the literature, we concluded that platelets could be critical links in propagafing antibody inifiated inflammation. Experiments using skin allografts allowed us to visualize the engagement of platelets by alloantibodies. Immunohistology demonstrated that alloantibodies are associated with the release of von Willebrand factor (vWO and P-selectin from endothelial cells. Platelets express receptors for both vWf and P-selectin. Our hypothesis is that antibodies initiate platelet responses that augment leukocyte interactions with endothelial cells in the transplant and that complement activafion products intensify each of these interactions. This project is designed to examine interactions of antibody and complement with endothelial cells, platelets and leukocytes in the following 3 specific aims: 1) Determine the effects of antibodies and complement on the localization and activation of platelets in renal transplants; 2) Determine the effects of platelet and complement activation on localization and activation of neutrophils, macrophages and T cells in transplants; and 3) Determine the effects of platelets and complement activation on alloantibody-induced rejection. To accomplish these specific aims, we will use a combinafion of models developed by the leaders of all 3 projects. For Specific Aims 1 and 2, we will use our model in which monoclonal anfibodies are passively transferred to SCID recipients of renal allografts. SCID mice permit complete control of the dose, fiming, anfigenic specificity and isotype of the anfibodies under investigafion in the absence of confounding additional responses from T cells or B cells. For Specific Aim 3, we will take advantage of models based on extensive work of Dr. Rob Fairchild in Project 1 and Dr. Anna Valujskikh in Project 3. In these models mice produce high titers of alloantibodies that cause complete rejection of renal transplants. Using these models, we will test the effects of depleting platelets on acute and chronic rejection. These are clinically relevant models that will provide data of mechanisfic and therapeufic importance.