NLRC5对Prdm1的表达调控在诱导肝移植免疫耐受中的作用及机制

Induction of immune tolerance is the most important modality to improve long-term survival of the transplant recipient. Transplant rejection is mainly mediated by T cells. NLRs family is significantly up-regulated during transplant rejection. In preliminary experiments we showed that the inhibition of NLRC5 could prolong the allograft survival in murine heart transplant model. NLRC5 could also promote IFN-γ and IL17 production, suppress IL-10 and Foxp3 production in vitro. Moreover, NLRC5 could regulate Prdm1 expression at transcriptional level, and Prdm1 could inhibit T cell response and induce T cell tolerance. Therefore, we hypothesize that blocking of NLRC5 may regulate CD4+ T cell function through Prdm1 and induce liver transplant tolerance. In the current study, we aim to establish the liver transplant model using NLRC5 conditional knockout mice, observe allograft survival, analyze the infiltrating CD4+ T cells function and sort them out for RNA-Sequencing, test the effect of NLRC5 on CD4+ T cell differentiation in vitro and in adoptive transfer model in vivo, verify how NLRC5 regulate the Prdm1 expression and whether the function of NLRC5 depends on Prdm1 using NLRC5 Prdm1 double conditional knockout mice, and finally exploit the potential of NLRC5 as a biomarker in the early diagnosis of transplant rejection in patients. The project will help to expand our understanding in the mechanism of transplant rejection, and provide a novel potential target for the clinical treatment of immune rejection.

诱导免疫耐受是提高移植受者长期存活的重要手段。近期研究发现，NLRs家族在移植排斥中呈显著上调。我们预实验显示抑制NLRC5能延长小鼠心脏移植物存活；在体外CD4+T细胞中NLRC5能增强IFN-γ及IL-17、抑制IL-10及Foxp3表达。最新研究提示NLRC5可调控Prdm1的表达，而Prdm1可抑制T细胞反应，促进T细胞耐受。由此我们推测，阻断NLRC5可通过Prdm1调控CD4+T细胞功能诱导移植免疫耐受。本课题拟采用NLRC5敲除小鼠建立肝移植模型，观察移植物存活情况，通过体内、外实验检测NLRC5对CD4+T细胞功能的影响；进而在分子水平上检测NLRC5对Prdm1的调控作用，并利用NLRC5 Prdm1双敲除小鼠观察是否具有依赖性；最后在移植患者中验证NLRC5早期诊断或预测排斥反应的可行性。本项目的开展将有助加深我们对移植排斥机制的认识，为发现新型药物治疗靶点提供科学依据

器官移植是目前治疗各类终末期疾病最有效手段之一，诱导免疫耐受是提高移植受者长期存活的重要手段。近期研究提示NLRs家族在移植排斥中呈显著上调；NLRC5可调控Prdm1的表达，而Prdm1可抑制T细胞反应，促进T细胞耐受。在本项目的研究中，我们已采用NLRC5敲除小鼠建立肝移植模型，观察移植物存活情况，通过体内、外实验检测了NLRC5对CD4+T细胞功能的影响；进而在分子水平上检测了NLRC5对Prdm1的调控作用，并利用NLRC5 Prdm1双敲除小鼠观察依赖性；最后在移植患者中验证了NLRC5早期诊断或预测排斥反应的可行性。我们的研究显示，阻断NLRC5可通过Prdm1调控CD4+T细胞功能诱导移植免疫耐受。抑制Prdm1会促进排斥反应的发生；而抑制NLRC5或过表达Prdm1后可延长移植物存活时间，诱导移植免疫耐受形成。本课题探索了一种新的免疫耐受诱导方法及其机制，为寻找干预移植排斥反应新途径提供了新的科学依据。目前，本项目已发表论著16篇（通讯作者），已获得授权的国家专利2项。