趋化因子受体CCR9和CCR7的协同作用触发浆细胞样树突状细胞介导移植耐受的机制

本课题利用趋化因子受体CCR7及CCR9基因缺陷小鼠开展实验，研究浆细胞样树突状细胞（pDCs）介导移植耐受的免疫学机制。课题组成员前期研究表明：野生型pDCs呈递移植耐受抗原，能够挽救CCR7及CCR9基因缺陷小鼠对移植耐受治疗的敏感性，但具体免疫学机制未明。本课题在体外细胞培养、同种异体小鼠心脏移植模型基础上，采用免疫组织学、流式细胞术、免疫分子生物学及过继免疫治疗等手段进行研究。研究pDCs呈递移抗原导致实体器官移植耐受的免疫学机制，期望能够证实如下假设：在移植耐受诱导治疗下，一种分子机制（即：CCR9协同 CCR7）在介导pDCs 呈递移植耐受抗原过程中起着关键作用，通过激活ICOS-B7RP1共刺激信号通路，导致宿主淋巴结及移植物内产生和聚集大量具有重要免疫负性调节功能的ICOS阳性Tregs亚群，导致移植耐受。期望通过本研究，为临床诱导移植耐受提供更多的基础研究支持。

In this project, we hypothesized that chemokine receptor CCR7 and CCR9 coordination is crucially involved in the establishement of transplantation tolerance mediated by alloantigen-presenting pDCs.Furthermore,we hypothesized that CCR7 and CCR9 coordination mediates transplantation tolerance via activating ICOS-B7RP1 costimulatory pathway,which rusults in abundant ICOS positive regulatory T cells infiltrated into allografts and accumulated in recipient's peripheral lymph nodes. Preliminary experiment from our study group demonstrated that transfusion of wild-type alloantigen-presenting pDCs can rescue CCR7 and/or CCR9 deficient animal's sensitivity to tolerance induction treatment, although the exact mechanisms of it is still poorly characterized.To explore our hypothesis, CCR7 and/or CCR9 deficient mice are used and the immunological mechanisms of CCR7 and CCR9 coordination during plasmacytoid dendritic cells mediating transplantation tolerance are investigated. Experimental methods,including Immunohistology,flow cytometry, adoptive immunotherapy, and other molecular biological techniques are used in this project.