Xenotransplantation may become a clinical reality once we more fully understand the mechanisms of rejection and can consistently obtain xenograft survival without systemic toxicity. Although hyperacute rejection can now be abrogated, vascularized xenografts are still subject to acute vascular rejection, alternatively referred to as delayed xenograft rejection. This latter mode of rejection is associated with vascular-based inflammation, thrombocytopenia and the consumption of coagulation factors that may evolve to disseminated intravascular coagulation (DIC). In addition, cellular xenotransplantation procedures to induce tolerance by mixed chimerism are associated with widespread thrombotic vascular injury. The mechanisms underlying DIC and thrombotic microangiopathy in these settings are unclear. The mechanisms underlying DIC and thrombotic microangiopathy in these settings are unclear. Low levels of inflammatory mediators within vascularized xenografts, or potentially within the recipient vasculature after the infusion of xenogeneic cells, could promote vascular thrombosis. Molecular incompatibilities can also be shown between primate coagulation factors e.g. thrombin, and natural anti-coagulants e.g. thrombomodulin on xenogeneic leukocytes and endothelium We plan to identify and further characterize mechanisms underlying the development of coagulation disturbances and thrombotic responses in primates, temporally related to the transplantation of vascularized xenografts and/or infusion of xenogeneic cells from swine. Initially, xenoreactive antibody mediated pro-coagulant responses in the absence of complement will be defined in vitro and then studied in vivo. We will also demonstrate how xenogeneic cells cause platelet-aggregate formation. Molecular barriers relating to excessive thrombin generation, heightened platelet interactions with porcine sub-endothelial matrix associated von Willebrand factor the potential failure to regulate fibrinolysis will be then investigated in depth. Our data should indicate suitable pharmacological measures and gene therapeutic modalities for the control of thrombotic complications associated with organ and cellular xenotransplantation. This approach should establish whether disordered regulation of coagulation between discordant species will present yet another barrier to xenograft survival. Control of vascular inflammation and thrombosis should also promote establishment of mixed xenogeneic chimerism; to facilitate rigorous testing of mechanisms of immunological tolerance to vascularized xenografts. These studies will be judged successful if novel and clinically relevant pharmacological and genetic anti-thrombotic strategies develop from our future experimental observations.
Showing the most recent 10 out of 192 publications
