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Presenter: Burcin, Ekser, Pittsburgh, United States
Authors: Burcin Ekser
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Special problems associated with liver xenografts
Burcin Ekser
Pittsburgh, PA, United States
Pig liver xenotransplantation could bridge patients in acute liver failure (ALF) to allotransplantation. Currently, the orthotopic transplantation of genetically-engineered (GE) pig livers in baboons is associated with survival of <10 days, but this is longer than the median waiting time (6 days) of UNOS Liver Status 1 emergency listing for ALF. The main problem which precludes prolonged survival of GE pig livers is immediate loss of platelets after reperfusion that results in spontaneous internal bleeding in the baboon. However, no features of hyperacute rejection have been observed.
The underlying mechanisms causing thrombocytopenia are not fully understood. There is evidence from in vivo studies that suggest that (i) immediate platelet and platelet/WBC aggregation occurs in the blood (demonstrated on flow cytometry), (ii) platelet, platelet/WBC, and platelet/fibrin aggregates develop within the liver sinusoids and also (iii) in the host lungs (both demonstrated by immunohistology and electron microscopy).
Studies of ex vivo pig liver perfusion with human blood indicate that human platelet phagocytosis may occur, mainly by the pig liver sinusoidal endothelial cells but also possibly by pig hepatocytes. Ex vivo and in vitro studies demonstrate significant reduction of platelet aggregation and phagocytosis by blocking various pathways, such as those involving integrin adhesion (by eptifibatide and anti-αMβ2 integrin antibody) and asialoglycoprotein receptor 1 (by anti-ASGR1 antibody). A pilot pig liver ex vivo study in baboons also investigated the interaction of GpIb with vWF and demonstrated a limited beneficial effect of anti-GpIb on immediate loss of platelets.
Playing roles in the development of thrombocytopenia may be (i) incompatibility of signal-regulatory protein alpha (SIRPα)-CD47 interaction between pig hepatic macrophages and recipient platelets, (ii) interaction between porcine von Willebrand factor (expressed by pig liver sinusoidal endothelial cells) and recipient platelets, resulting in activation and aggregation of platelets, and (iii) porcine CD18 receptor on Kupffer cells being involved in human platelet phagocytosis.
Translation of ex vivo and in vitro experiments to the pig-to-baboon liver transplantation model is required to determine whether thrombocytopenia can be prevented or reduced, thus prolonging host survival. If this problem can be resolved, then bridging to allotransplantation may be feasible. What is encouraging is that GE pig livers appear to function adequately in immunosuppressed baboons until the effects of thrombocytopenia become problematic.
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