急性排斥反应是影响肝移植成功和移植物长期存活的关键因素之一。我们在前一个项目中证实了Th17在排斥反应中的重要作用,并通过干预转录因子Batf抑制Th17分化和排斥反应的发生。然而，我们及其他学者的研究均证实，排斥反应是Th1和Th17共同作用的结果。从调控巨噬细胞活化状态入手，将有可能同时抑制Th1和Th17反应，从而更好的控制排斥反应。因此，申请者拟采用Micro-array，基因过表达/敲减及免疫共沉淀等技术，在大鼠肝移植模型及体外实验中，研究USP25对巨噬细胞活化状态的调控，以及巨噬细胞不同活化状态对Th分化及移植肝内炎症细胞浸润的影响；寻找巨噬细胞内USP25的作用靶点，阐明其调控巨噬细胞活化的分子机制；并通过干预USP25，调控巨噬细胞，观察其对排斥反应的影响，丰富目前的移植免疫理论，为防治肝移植排斥反应提供新策略。

Allograft rejection, which is commonly caused by cellular immunity, is one of the most important reasons affecting success and long-term survival of recipients of liver transplantation. Our previous research reported that the Th17 cells contributed to the development of rejection in solid organ transplantation via direct and indirect pathways. We decreased the rejection rates by targeting Batf pathway via inhibition of Th17 activity. However, lots of research had demonstrated that both Th1 and Th17 cells were involved in the cellular mechanism of acute rejection. The therapies that simultaneously target Th1 and Th17 could be more efficient in controlling the rejection. In this project, we will apply micro-array, knock-in/ knockdown and immunoprecipitation to identify the effect of ubiquitin-specific protease 25 (USP25) in regulating the activation pattern of macrophage, and following Th cells activation and tissue infiltration in rat liver transplantation model. We will figure out the molecular mechanism of USP25 in the activation pathways in macrophage. Meanwhile, we will use USP25 as an immunotherapy target, to regulate the activation status of macrophages and control the rejection of liver transplantation. This study may improve our knowledge of transplant immunology and provide potential approaches for attenuating rejection in liver transplantation.