Xenogeneic Hepatocyte Transplantation for Cirrhosis

超出所提供的空间。！绝大多数等待器官移植的患者有终末期慢性肝病继发性肝硬化。与器官移植相比，肝细胞移植有几个重要的优势，最近的研究表明，肝细胞移植可以延长啮齿动物的生存期，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随后移植的人类肝脏数量有限。人类供体可用性问题的一个可能解决方案是猪肝细胞移植。关于在人体内使用猪肝细胞的两个主要问题涉及异种肝细胞在多大程度上可以恢复肝功能障碍患者的正常肝脏生理，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给肝硬化大鼠的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反应因物种而异，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。本研究的目的是：1)检测猪肝细胞移植对肝硬化非人灵长类动物肝功能的改善程度；2)观察猪肝细胞是否对蚂蚁介导的排斥反应敏感！-猪抗体并检测灵长类动物对猪肝细胞的免疫反应在肝硬化和非肝硬化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)免疫复合物的形成，b)凝血/补体系统的激活和c)免疫致敏，这可能会阻止以后的同种异体移植。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. !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. PERFORMANCE SITE ========================================Section End===========================================