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Pig endothelial responses in vascularized xenografts

Simon C. Robson

Transplant Institute, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, United States

Xenotransplantation will become clinically feasible once innate and adaptive mechanisms of xenograft loss and rejection are better understood and more approprately addressed. Vascular endothelial cell activation by natural and elicited antibodies, complement, platelet thrombotic processes and lymphocytes, amongst other insults, results in manifestations of microangiopathy culminating in vascularized graft injury and variable coagulation disturbances. We have made significant progress in defining mechanisms of consumptive coagulopathy in xenotransplantation linked to associated functional incompatibilities of CD39 and thrombomodulin across species, and by determining novel vascular markers of injury associated with humoral rejection. Adenosine generated by ectonucleotidases blocks platelet activation impeding coagulation and also serves as an immune suppressive mediator. Thrombomodulin also has both thromboregulatory properties and anti inflammatory potential afforded by thrombin catalytic changes and activated protein C generation.

Our overall goal is to limit xenograft injury and promote tolerance by targeting common mediators of vascular inflammation, innate and adaptive immunity by generation of novel transgenic swine and testing these in models of pig-to-primate xenotransplantation. Successful expression of these human thromboregulatory factors by transgenesis might bring xenotransplantation closer to clinical application. Our studies further provide insights into the regulation of thrombosis and vascular injury, within transplanted organs and in a wide arrange of inflammatory and malignant conditions.