The proposed research tests whether swine hepatocyte xenografts can improve survival in acute or fulminant liver failure. Acute liver failure poses an extraordinary clinical challenge. This challenge reflects in part the complex, life-threatening pathophysiology of the condition. However, it also reflects the view that approximately one third, and possibly more of those most severely afflicted with acute liver failure, could recover liver function if effective artificial or biological support were available. Instead, these patients typically undergo emergency orthotopic liver transplantation or they die. Anecdotal reports in humans and experiments in animals suggest that transplantation of isolated hepatocytes into the damaged liver, by infusion in the portal vein, might obviate the need for organ transplantation in patients with liver failure. Since human livers are in short supply, interest has focused on use of hepatocytes from animals, especially swine, the hepatocytes of which are sometimes incorporated in artificial liver support devices. Our research employs the first reproducible model of acute liver failure in non-human primates and new approaches to imaging grafted cells and assaying immune responses that ensue. With these innovations, the proposed research will reveal, in a pre-clinical setting, 1) the extent to which swine hepatocyte xenografts can support life and reverse the key pathophysiologic manifestations of acute liver failure, 2) whether immune or non-immune barriers limit the impact of the grafts or cause the grafts to fail, and 3) the conditions in which failure can be reversed b increased immunosuppression and/or provision of another hepatocyte xenograft. Besides potentially providing proof of principle, the research may advance broader application of the model of acute liver failure, approaches to tracing the fate of grafted cells and the immune response they provoke.
The project evaluates in a pre-clinical model the potential use of liver cell (hepatocyte) xenografts for treatment of patients with severe acute liver failure. Patients with severe acute liver failure currently must undergo emergency liver transplant, even though some, perhaps 30%, could recover liver function if they could be kept alive for a period of months. A hepatocyte xenograft could avert the need for a liver transplant, thus sparing the patient from lifelong immunosuppressive therapy and allowing the scarce donated human livers to be used for others in need of a liver transplant.
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