Xenogeneic Hepatocyte Transplantation for Cirrhosis

描述(由申请人提供)： 绝大多数等待器官移植的患者都患有继发于肝硬变的终末期慢性肝病。与器官移植相比，肝细胞移植具有许多重要的优点，近年来研究表明，肝细胞移植可以延长啮齿动物的存活时间，改善与肝硬变和终末期肝病相关的生理异常。然而，可用于肝细胞分离和随后移植的人体肝脏数量有限。人类供体可获得性问题的一个可能的解决方案是移植猪的肝细胞。关于猪肝细胞在人类体内应用的两个主要问题涉及异种肝细胞能在多大程度上恢复肝功能障碍患者的正常肝生理，以及对肝细胞或其产物的免疫反应。初步研究表明，可能不需要免疫抑制来改善移植到肝硬变大鼠体内的同种异体大鼠或猪肝细胞的存活或功能。然而，猪肝细胞的特异性抗体和细胞免疫反应因物种不同而不同，猪肝蛋白在人体内的特异性生理相容性和功能尚不清楚。我们现在建议在灵长类动物模型中扩展我们的观察，这将作为临床应用的前奏。这项建议的目的是：1)测试猪肝细胞移植在多大程度上可以改善肝硬变非人类灵长类动物的肝功能；2)检查猪肝细胞是否对抗猪抗体介导的排斥反应敏感，并测试对猪肝细胞的灵长类免疫反应在肝硬变和非肝硬变受体中是否有显著差异；3)确定猪肝细胞移植是否会导致系统性并发症，包括a)免疫复合体的形成，b)凝血/补体系统的激活和c)免疫致敏，可能阻止以后的同种异体移植。

DESCRIPTION (provided by applicant): The vast majority of patients awaiting organ transplantation have end-stage chronic liver disease secondary to cirrhosis. Hepatocyte transplantation has several important advantages over organ transplantation and was recently shown to prolong the survival and improve the physiologic abnormalities associated with cirrhosis and end-stage liver disease in rodents. The number of human livers available for hepatocyte isolation and later transplantation, however, is limited. One possible solution to the human donor availability issue is transplantation of hepatocytes from pigs. Two major concerns regarding the use of porcine hepatocytes in man relate to the degree to which xenogeneic hepatocytes can restore normal liver physiology to patients with liver dysfunction and the immunological response to liver cells or their products. Preliminary studies indicate that immunosuppression may not be needed to improve the survival or function of allogeneic rat or pig hepatocytes transplanted in cirrhotic rats. However, specific antibody and cellular immune responses to pig hepatocytes vary by species and the specific physiologic compatibility and function of pig liver proteins in man is unknown. We now propose to extend our observations in a primate model that will serve as a prelude to clinical application. The aims of this proposal are: 1) To test the degree to which porcine hepatocyte transplantation can improve liver function in cirrhotic non-human primates; 2) To examine whether pig hepatocytes are susceptible to rejection mediated by anti-swine antibodies and test whether the primate immune response to porcine hepatocytes is significantly different in cirrhotic versus non-cirrhotic recipients; and 3) To determine whether porcine hepatocyte transplantation leads to systemic complications that include a) immune complex formation, b) activation of the coagulation/complement system and c) immune sensitization that may preclude later allotransplantation.