Xenogeneic Hepatocyte Transplantation for Cirrhosis

异种肝细胞移植治疗肝硬化

• 批准号: 6686109
• 负责人: Ira J. Fox
• 金额: $ 22.36万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686109
• 关键词: Macaca fascicularis; cell transplantation; complement pathway; enzyme linked immunosorbent assay; histocompatibility; immune complex; immunocytochemistry; immunosuppression; in situ hybridization; liver cells; liver cirrhosis; liver function; nonhuman therapy evaluation; swine; transplant rejection; transplantation immunology; xenotransplantation

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.

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。与器官移植相比，肝细胞移植有几个重要的优点，最近被证明可以延长啮齿动物的生存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随后移植的人类肝脏的数量是有限的。解决人类供体可用性问题的一种可能的解决方案是移植猪的肝细胞。关于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机能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肝硬化大鼠移植的同种异体大鼠或猪肝细胞的存活或功能。然而，针对猪肝细胞的特异性抗体和细胞免疫反应因物种而异，并且猪肝蛋白在人类中的具体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。该提案的目的是：1）测试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) 检查猪肝细胞是否容易受到抗猪抗体介导的排斥反应，并测试灵长类动物对猪肝细胞的免疫反应在肝硬化与非肝硬化受者中是否存在显着差异； 3) 确定猪肝细胞移植是否会导致全身并发症，包括a) 免疫复合物形成，b) 凝血/补体系统激活，以及c) 可能妨碍以后同种异体移植的免疫敏化。