Repopulation of Liver Allografts by Recipients

描述(由申请人提供)：成功的肝移植可以跨越许多菌株组合中主要组织相容性复合体(MHC)的差异，临床研究表明，在一些肝移植接受者中，免疫抑制可以完全取消，而不会产生不良反应。成人肝脏的再生足够强大，可以成功移植缩小大小的肝脏。有趣的是，与标准的全肝移植相比，部分肝移植受者的排斥反应发生率和维持免疫抑制的剂量可能会减少。确定创造这样一种特权免疫环境的机制与临床移植有关。最近的研究表明，骨髓干细胞可能具有比之前所认识到的更广泛的分化潜力。这些令人困惑的观察结果导致了一种假设，即造血干细胞(HSCs)可能能够修复全身受损的组织。我们的中心假设是，部分同种异体肝移植增加了再生刺激，促进了含有受体来源的祖细胞的同种异体肝移植物中细胞室的再生，而涉及受体干细胞的肝再生是导致嵌合性肝和长期接受的关键机制。我们推测，免疫抑制可能会对移植肝的再生产生不利影响。通过建立大鼠全肝和部分(50%)原位肝移植模型，研究受体MHC阳性肝细胞在移植后肝组织中出现的机制，比较排斥模型和接受模型中移植肝再生的差异，确定Kupffer细胞在移植肝再生中的作用，以及免疫抑制对供者再生的影响。我们的研究可能对促进肝移植后耐受和再生的机制提供新的见解，并将为开发新的治疗方法提供基础。

DESCRIPTION (provided by applicant): Successful liver transplantation can be performed across major histocompatibility complex (MHC) disparities in a number of strains combinations, and clinical studies have shown that immunosuppression can be completely withdrawn in some liver allograft recipients without adverse effects. Regeneration of adult liver is sufficiently robust to permit successful transplantation of reduced size liver grafts. Interestingly, the incidence of rejection and dose of maintenance immunosuppression may be diminished in recipient of partial liver transplants compared to standard whole liver allograft. Defining the mechanisms which create such a privileged immunological environment is relevant to clinical transplantation. Recent studies have suggested that bone marrow stem cells might possess a much broader differentiation potential than previously appreciated. These perplexing observations have led to the hypothesis that hematopoietic stem cells (HSCs) might be able to repair damaged tissue throughout the body. Our central hypothesis is that repopulation of cellular compartments in the hepatic allograft with recipient-derived progenitor cells is promoted by the increased regenerative stimulus of partial hepatic allografts, and that hepatic regeneration involving recipient stem cells is a key mechanism resulting in a chimeric liver and long term acceptance. We speculate that immunosuppression may influence the repopulation of liver allografts adversely. Using rat orthotopic whole and partial (50%) liver transplantation models, the mechanisms in which recipient MHC-positive hepatocytes appear in liver allografts after transplantation will be identified, the difference in repopulation of liver allografts between rejection and acceptance models will be compared, the role of Kupffer cells in repopulation of liver allografts will be determined, and the influence of immunosuppression on donor repopulation will be determined. Our studies may provide new insights into the mechanisms which promote tolerance and regeneration after liver transplantation and will provide the basis for the development of novel therapies.