Hepatocyte xenografts for treatment of acute liver failure

 描述(由申请人提供)：建议的研究测试猪肝细胞异种移植是否可以提高急性或暴发性肝衰竭的存活率。急性肝功能衰竭 构成了一个非同寻常的临床挑战。这一挑战在一定程度上反映了这种疾病复杂的、危及生命的病理生理。然而，它也反映了这样一种观点，即如果获得有效的人工或生物支持，大约三分之一，甚至可能更多患有急性肝衰竭的最严重的患者，可以恢复肝功能。 相反，这些患者通常会接受紧急原位肝移植，否则就会死亡。人类的轶事报道和动物的实验表明，通过门静脉输注将分离的肝细胞移植到受损的肝脏中，可能会消除肝功能衰竭患者进行器官移植的需要。由于人类肝脏供不应求，人们的兴趣主要集中在使用动物的肝细胞，特别是猪的肝细胞，这些肝细胞有时会被纳入人工肝支持装置中。我们的研究采用了第一个可在非人类灵长类动物中复制的急性肝功能衰竭模型，以及成像移植细胞和分析随后的免疫反应的新方法。通过这些创新，拟议的研究将在临床前环境中揭示：1)猪肝细胞异种移植在多大程度上能够维持生命并逆转急性肝衰竭的关键病理生理表现；2)免疫或非免疫屏障是否限制了移植物的影响或导致移植物失败；3)失败可以通过增加免疫抑制和/或提供另一种肝细胞异种移植来逆转的条件。除了可能提供原则性证据外，这项研究还可能推动急性肝功能衰竭模型的更广泛应用，追踪移植细胞的命运及其引发的免疫反应的方法。

 DESCRIPTION (provided by applicant): 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.