THE ROLE OF COMPLEMENT IN XENOTRANSPLANTATION

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The overall objective is to elucidate the role of complement in the pathogenesis of xenograft rejection. It is well established that complement activation plays a key role in hyperacute xenograft rejection and its believed that the mechanism of damage of pig xenograft in primates is mediated by natural antibody and the classical complement pathway. Xenografts that survive hyperacute rejection may be destroyed some days later by a process termed acute vascular rejection. The histology of acute vascular rejection is identical to that of hyperacute rejection and we hypothesize that cobra venom factor does not complement components activated by the CVF in small amounts to the graft. This project uses novel complement inhibition and inactivation to prevent complement binding to graft endothelium, studies the effect of complement binding in endothelial cell activation, and examines the binding of immunologically active materials to the graft in such a way as to inhibit or delay acute vascular rejection. These experiments represent an approach to acute vascular rejection using more extensive complement inhibition incorporating agents which activate and inhibit complement. The second aim is to elucidate the mechanism by which antibody and complement binding to grafts initiate graft rejection. The effect of binding of complement proteins to endothelial monolayers and generation of complement activation products will be examined. Cytokine production will be monitored as to explore how complement binding and endothelial cell activation proceed. Finally, the process of accommodation will be examined. The interaction of grafts with antibody and complement under some circumstances appears to protect graft from further damage in several experimental models. The mechanism of this effect will be explored with particular emphasis on the binding of complement degradation fragments to critical graft sits in such a way that the binding of further active complement products is inhibited.