Repopulation of Liver Allografts by Recipients

描述（由申请人提供）：成功的肝移植可以在许多菌株组合中跨越主要组织相容性复合体（MHC）差异进行，临床研究表明，在一些同种异体肝移植受体中，免疫抑制可以完全撤销而无不良反应。成人肝脏的再生足够强健，可以成功移植小尺寸的肝移植。有趣的是，与标准的同种异体全肝移植相比，部分肝移植受体的排斥发生率和维持免疫抑制剂量可能会降低。确定创造这种特殊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以前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造血干细胞（hsc）可能能够修复全身受损组织的假设。我们的中心假设是，部分肝脏移植增加的再生刺激促进了受体来源的祖细胞在肝移植物中的细胞区室的再生，并且涉及受体干细胞的肝再生是导致嵌合肝脏和长期接受的关键机制。我们推测免疫抑制可能对同种异体肝移植的再生产生不利影响。利用大鼠原位全肝和部分（50%）肝移植模型，确定移植后受体mhc阳性肝细胞在同种异体肝移植中出现的机制，比较排斥模型和接受模型在同种异体肝移植再生中的差异，确定Kupffer细胞在同种异体肝移植再生中的作用，确定免疫抑制对供体再生的影响。我们的研究可能为肝移植后促进耐受性和再生的机制提供新的见解，并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in a number of strains combinations, and clinical studies have shown that immunosuppression can be completely withdrawn in some liver allograft recipients without adverse effects.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.