调控供体肝源性抗原提呈细胞的DAP12/TREM2诱导肾移植免疫耐受及机制研究

供体特异性免疫耐受是肾移植的终极目标，而排斥反应及移植肾纤维化严重阻碍着免疫耐受的实现，从肝移植自发性免疫耐受中借鉴新的策略是诱导肾移植免疫耐受的新思路。我们前期发现DAP12/TREM2在肝脏树突状细胞（DC）和巨噬细胞（Mø）中高表达，增强其免疫调节功能；供体肝脏DAP12通过cross-dressing DC（CD-DC）促进小鼠肝移植耐受。故本项目拟上调供体肝源性DC和Mø的DAP12，诱导具有更强免疫调节功能的DAP12 high DCreg和DAP12 high M2，静脉输注到肾移植受体诱导免疫耐受；并通过双光子活体成像等方法，研究DAP12/TREM2调控CD-DC及PDL1来抑制T细胞应答的机制，探讨DAP12促进M2极化进而预防移植肾纤维化，及其对TREM2的依赖性等机制。本研究在不使用免疫抑制剂的情况下，采用细胞联合治疗诱导肾移植耐受，将为耐受诱导提供全新的理论基础。

Donor-specific immune tolerance is the ultimate goal for kidney transplantation, however the rejection and renal graft fibrosis seriously hinder the realization of immune tolerance. Our previous studies have shown that TREM2 and DAP12 highly expressed on liver-derived dendritic cells (DC) and macrophages (Mø), which enhanced their immune-regulatory function. Donor liver DAP12 could promote liver transplant tolerance in mice through cross-dressing DC (CD-DC). Therefore, this project intends to up-regulate the DAP12 expression on the donor liver-derived DC and Mø to induce DAP12 high DCreg and DAP12 high M2 with stronger immune-regulatory function. Intravenous injection of DAP12 high DCreg and DAP12 high M2 into kidney transplant recipients could induce immune tolerance. We will utilize the intra-vital two-photon imaging technique and other methods to dig out the mechanisms regarding DAP12/TREM2 regulate CD-DC and PDL1 to suppress T cell response. We will explore the mechanisms regarding DAP12 promotes M2 polarization to prevent renal allograft fibrosis and their dependence on TREM2. In this study, .combined cell therapy in the absence of immunosuppression to induce kidney transplant tolerance will provide a novel theoretical basis for tolerance induction.