Xenogeneic Hepatocyte Transplantation for Cirrhosis

绝大多数等待器官移植的患者患有终末期慢性肝病继发性 伊藤肝硬化肝细胞移植相对于器官移植有几个重要的优点， 最近被证明可以延长生存期并改善与以下相关的生理异常： 啮齿类动物的肝硬化和终末期肝病。可供肝细胞移植的人类肝脏数量 然而，隔离和随后的移植是有限的。一个可能的解决办法是， 问题是猪肝细胞的移植。关于使用猪的两个主要问题 人类肝细胞的数量与异种肝细胞恢复正常肝脏的程度有关 肝功能障碍患者的生理学和对肝细胞或其产物的免疫应答。 初步研究表明，免疫抑制可能不需要改善生存或功能 同种异体大鼠或猪肝细胞移植到患肝硬化的大鼠体内。然而，特异性抗体和细胞 对猪肝细胞的免疫应答因物种和特定的生理相容性和功能而异 猪肝蛋白在人体内的含量是未知的。我们现在建议在灵长类动物模型中扩展我们的观察， 将作为临床应用的前奏。本提案的目的是：1）测试 猪肝细胞移植可以改善非人灵长类动物的肝功能; 2）检查 猪肝细胞是否对蚂蚁介导的排斥反应敏感，猪的抗体，并测试是否 灵长类动物对猪肝细胞的免疫应答在阿尔茨海默病与非阿尔茨海默病中显著不同， 确定猪肝细胞移植是否导致全身并发症 其包括a）免疫复合物形成，B）凝血/补体系统的活化和c） 免疫致敏可能会妨碍以后的同种异体移植。

The vast majority of patients awaiting organ transplantation have end-stage chronic liver disease secondary Ito 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 Icirrhosis 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 Ihepatocytes 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 ant!-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.