Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Co-Stimulation Blockade

摘要

Since the first attempt in 1968, survival following pig-to-primate liver xenotransplantation (LXT) has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous post-transplant infusion of human prothrombin concentrate complex and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone and co-stimulation blockade (belatacept, n=3 or anti-CD40mAb, n=1) to extend survival. Baboon #1 remained well until POD25 when euthanasia was required due to cholestasis and plantar ulcers. Baboon #2 was euthanized following a seizure on POD5, despite normal LFTs and no apparent pathology. Baboon # 3 demonstrated initial stable liver function, but was euthanized on POD8 due to worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis and a focal CMV inclusion. Baboon # 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations as well as rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation or TMA. Thus, nearly one-month rejection-free survival has been achieved following LXT in 2 of 4 continuous recipients, demonstrating that the porcine liver can support life in primates for several weeks and is encouraging for potential clinical application of LXT as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.