Hepatocyte xenografts for treatment of acute liver failure

 描述（由申请方提供）：拟定的研究测试了猪肝细胞异种移植物是否可以改善急性或暴发性肝功能衰竭的存活率。急性肝衰竭 提出了一个非凡的临床挑战。这一挑战部分反映了该疾病复杂的、危及生命的病理生理学。然而，它也反映了这样一种观点，即如果有有效的人工或生物支持，大约三分之一，可能更多的最严重的急性肝功能衰竭患者可以恢复肝功能。 相反，这些患者通常接受紧急原位肝移植或死亡。在人类和动物实验中的轶事报告表明，通过门静脉输注将分离的肝细胞移植到受损的肝脏中，可能会减少肝功能衰竭患者对器官移植的需求。由于人类肝脏供应短缺，人们的兴趣集中在使用来自动物，特别是猪的肝细胞，其肝细胞有时被并入人工肝支持装置中。我们的研究采用了第一个可重复的非人灵长类动物急性肝功能衰竭模型和新的方法来成像移植细胞和测定随之而来的免疫反应。通过这些创新，拟议的研究将在临床前环境中揭示：1）猪肝细胞异种移植物可以支持生命并逆转急性肝衰竭的关键病理生理学表现的程度，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，和3）B增加免疫抑制和/或提供另一种肝细胞异种移植物可以逆转失败的情况。除了可能提供原理证明外，这项研究还可能推动急性肝衰竭模型的更广泛应用，追踪移植细胞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.