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患有继发于肝硬化的终末期慢性肝病。肝细胞移植与器官移植相比具有几个重要的优势，最近显示出可以延长啮齿动物的生存期，并改善与肝硬化和终末期肝病相关的生理异常。然而，可用于肝细胞分离和以后移植的人类肝脏的数量是有限的。人类供体可用性问题的一个可能的解决方案是从猪移植肝细胞。在人类中使用猪肝细胞的两个主要问题涉及异种肝细胞可以在多大程度上恢复肝功能障碍患者的正常肝脏生理学以及对肝细胞或其产物的免疫应答。初步研究表明，可能不需要免疫抑制来改善移植到肝硬化大鼠中的同种异体大鼠或猪肝细胞的存活或功能。然而，对猪肝细胞的特异性抗体和细胞免疫应答因物种而异，猪肝蛋白在人体中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。本研究的目的是：1）检测猪肝细胞移植对非人灵长类动物肝功能的改善程度; 2）检测猪肝细胞是否易受抗猪抗体介导的排斥反应，并检测在移植后的灵长类动物对猪肝细胞的免疫应答是否存在显著差异;和3）确定猪肝细胞移植是否导致全身并发症，包括a）免疫复合物形成，B）凝血/补体系统的激活和c）可能妨碍以后同种异体移植的免疫致敏。

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.