受体MDSCs通过CEACAM1-TIM3调控NK细胞功能介导肝移植免疫耐受的机制研究

The induction and maintenance of immune tolerance to transplanted tissue constitute an active process to prevent graft rejection. Liver allografts are accepted spontaneously in most combinations of mismatch in major histocompatibility complex, without any requirements for immunosuppression. Therefore, transplants in mice provide an informative model and valuable tool to study the mechanisms of tolerance induction and maintenance. The NK cells are expanded after allogeneic liver transplant and maintained at a higher level in the liver grafts and recipient spleens. This subset of NK cells may contribute to subsequent maintenance of tolerance. In different rodent tranplantation models, accumulation of MDSCs was observed in the allograft and spleens of recipient. And MDSCs can promote immune tolerance via NK cells. In our preliminary experiments, it was shown that MDSCs expanded in allograft and spleen after murine liver transplantation and may promote the formation of immune tolerance via regulating the function of NK cells. Recent studies suggest that MDSCs can express CEACAM1. CEACAM1 can induce T cell exhaustion and anergy via CEACAM1-Tim3 pathway. Our results showed that Tim-3 mainly expressed in NK cells from allograft. Based on these results, we will detect the level of MDSCs in transplanted liver for the first time as far as we know, and investigate the roles of CEACAM1-Tim3 pathway on the regulatory mechanism of MDSCs to NK cytotoxicity, cytokines expression and apoptosis. Through the research of this subject, we will further reveal the additional regulatory mechanism of the immune tolerance after liver transplantation and provide new strategies and targets for prevention and treatment of allograft rejection.

肝移植免疫耐受现象为研究器官移植免疫耐受的建立提供了新思路。NK细胞在诱导和维持肝移植免疫耐受中发挥着重要作用。在肾脏、心脏及皮肤移植的动物模型中发现有MDSCs的大量聚集，且MDSCs可以依赖NK发挥免疫抑制功能。我们前期结果发现在小鼠移植肝中MDSCs可以大量聚集。然而MDSCs在调节肝移植免疫耐受中的作用及其机制尚不清楚。最近的研究发现CEACAM1可以在MDSCs上表达，另外CEACAM1-Tim3通路可以调节T细胞耗竭和失能，进而发挥免疫调节作用。我们对发生免疫耐受小鼠移植肝中的NK进行检测，发现NK高表达Tim3。基于以上分析，本课题拟在前期研究基础上，首次分析受体小鼠移植肝MDSCs的水平，并围绕CEACAM1-Tim3通路探讨MDSCs对NK杀伤 、细胞因子表达及凋亡的调控作用，旨在进一步揭示肝移植免疫耐受的调节机制，为器官移植后获得稳定的免疫耐受提供新的策略及靶点。

NK细胞在移植肝脏中扩增并维持较高水平提示NK细胞可能在诱导和维持移植免疫耐受中发挥着重要作用。在移植动物模型的移植物中发现有MDSCs的大量聚集，且MDSCs可以依赖NK细胞发挥免疫抑制功能。CEACAM1-Tim3通路可以调节T细胞耗竭和失能，进而发挥免疫调节作用。本研究探究了在肝移植移植微环境中MDSCs对免疫耐受的调控及其相关机制，发现在移植免疫耐受微环境下MDSCs高表达，并通CEACAM1-Tim3通路影响NK细胞的作用和细胞因子分泌，从而介导免疫耐受。此外，在移植微环境中，一些特征性因子和移植后血管的排斥反应以及病变有密切关系。本研究发现RNA聚合酶I在移植后血管的病变中发挥了重要作用，这也为器官移植后避免移植血管损伤和病变提供了新思路。移植免疫耐受微环境和恶性肿瘤生长、侵袭微环境存在高度相似性。为了进一步验证CEACAM1-TIM3通路在诱导免疫耐受中的作用，本研究探究了CEACAM1-Tim3通路在肝癌细胞的侵袭和增殖中的作用。研究发现，Tim3可以通过抑制NK细胞作用促进肝癌细胞的增殖，并可以增强其侵袭性，而CEACAM1对Tim3表达有调节作用。总之，本研究从多角度探究了MDSCs在免疫微环境中的免疫调节作用，尤其首次发现CEACAM1-Tim3通路在调控NK杀伤作用和细胞因子分泌中发挥的重要作用，为移植免疫耐受及肿瘤免疫逃逸相关机制的理解做出了有价值的补充。