转位蛋白（TSPO）配体对抗体介导免疫排斥反应的防治作用及其机制的研究

Antibody-mediated rejection (AMR) has emerged as the major cause of renal allograft dysfunction. The reasons induced to AMR are that complement activated by donor-specific antibody (DSA) and the infiltration of immune cells in kidney. But the definite mechanism has not been known and more effective strategies need to be explored for improving transplant outcomes. The translocator protein (TSPO 18kDa) is localized predominantly on the membranes of immune cells. TSPO ligand, high-affinity to TSPO，can regulate the immune function. We found that TSPO ligand inhibited the secretion of IgG by B cells in vitro and reduced the donor-specific antibody in skin allograft model in vivo. Morever, we discovered that TSPO ligand prolonged the survival time of allografts and reduced the inflammatory infiltration in skin allograft model. These evidences were all strongly suggested that TSPO ligand may be a new avenue for treating AMR. This project will comprehensively explore the therapeutic effects of TSPO ligand on mouse renal allograft of AMR based on the previous study. After treated with TSPO ligand, we will further investigate the inflammatory infiltration, cell activation, expression of transcription factors, cytokine secretion, antibody production and complement activation in the allograft. Our research may explore a new strategy for the treatment of AMR and improve further understandings about the pathogenesis.

抗体介导排斥（AMR）是影响肾移植远期存活的首要原因，B细胞分泌抗供体特异性抗体激活补体及免疫细胞在移植肾区大量浸润参与并加速AMR的进程，然而现有的治疗手段尚不理想。新近研究发现转位蛋白（TSPO）作为免疫细胞膜结构的一部分，其与配体的结合有很强的免疫调节功能。我们在前期研究结果中发现TSPO配体可抑制B细胞增殖及抗体的分泌，在皮肤移植小鼠模型中降低抗供体特异性抗体水平。与此同时我们还证实了TSPO与配体结合可减少炎细胞在移植皮瓣区浸润，抑制皮肤移植排斥反应的发生，延长移植皮瓣生存时间。这些都强烈提示TSPO配体可能在抑制AMR发生发展中具有重要作用。本项目拟在现有研究基础上，构建小鼠AMR模型，进一步从细胞浸润类型、活化程度、细胞因子产生及转录因子表达，抗体产生、补体激活等多方面入手，深入探讨TSPO配体对AMR防治效果及治疗机制，以期为AMR找到新的治疗手段。

抗体介导的排斥反应（antibody mediate rejection, AMR）是导致远期移植物失功的主要原因，现有治疗手段尚不理想。本研究通过构建大鼠心脏移植急性AMR模型证实了TSPO对AMR的防治作用，体内实验中，TSPO的配体显著延长移植物的存活时间；体外实验中，TSPO的配体显著抑制B细胞的分裂增殖和抗体的产生。TSPO位于线粒体膜上，对糖酵解调控分子PDK1和线粒体呼吸链复合体I、II、IV都有上调表达和促进功能的作用。TSPO配体与TSPO结合抑制了B细胞糖酵解和线粒体呼吸的能力，使得B细胞分化和抗体分泌的能力降低，进而在体内抑制DSA的产生，达到防治AMR的目的。本研究证实了TSPO配体在器官移植中防治AMR的应用价值，并阐明了其通过代谢调控来发挥作用的机制，为移植临床解决AMR提供了新的思路和药物靶点。此外，我们还探究了TLR9在小鼠慢性纤维化中的作用；雷公藤甲素、青蒿素和羟氯喹分别在移植物血管病、细胞介导的排斥反应和缺血再灌注损伤中的作用。.项目发表相关SCI论文4篇，IF均大于5，中文综述2篇，培养博士研究生1名。