Xenogeneic Hepatocyte Transplantation for Cirrhosis

绝大多数等待器官移植的患者都是继发性终末期慢性肝病。 伊藤硬化症。与器官移植相比，肝细胞移植有几个重要的优势 最近被证明可以延长存活时间并改善与之相关的生理异常 啮齿动物的肝硬变和终末期肝病。可供肝细胞使用的人体肝脏数量 然而，隔离和后来的移植是有限的。人类供体可用性的一个可能的解决方案 问题是从猪身上移植肝细胞。关于使用猪的两个主要问题 人的肝细胞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反应。 初步研究表明，可能不需要免疫抑制来改善存活率或功能 同种异体大鼠或猪肝细胞移植到肝硬变大鼠体内。然而，特异性抗体和细胞 对猪肝细胞的免疫反应因物种和特定的生理配伍和功能而异 猪肝蛋白在人类体内的含量尚不清楚。我们现在建议在灵长类动物模型中扩展我们的观察 将作为临床应用的前奏。这项提议的目的是：1)测试在何种程度上 猪肝细胞移植可改善肝硬变非人灵长类动物的肝功能；2)检测 猪肝细胞是否对蚂蚁-猪抗体介导的排斥反应敏感，并测试 肝硬化组和非肝硬化组灵长类动物对猪肝细胞的免疫反应明显不同 受者；以及3)确定猪肝细胞移植是否导致全身并发症 这包括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，可能会阻止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.