SIGIRR联合SOCS1负调控TLR-IL-1R炎症信号通路诱导肝移植免疫耐受作用及其机制

We have previously found that though graft survival can be prolonged either by blocking the OX40 costimulatory signal in T cells or by adoptive transfer of donor derived dendritic cells (DC) with high expression of BTLA, a molecule that negatively regulates T cell activation, the implanted grafts are still rejected. To increase the success rate of induction of immune tolerance is a key method to improve long-term prognosis in transplant recipients. Research investigating the effect of inflammatory signal transduction in transplantation rejection is an emerging field of immunology. Intragraft inflammation was found to promote DC maturation and Th cell differentiation and proliferation via the TLR-IL-1R pathway, thus initiate and strengthen the immune response. SIGIRR and SOCS1 are negative regulators of the TLR-IL-1R pathway and may exert synergistic effects. In preliminary experiment we have showed that over expression of SIGIRR may reduce the inflammation reaction of H292 cells which induced by LPS, and overexpression of SOCS-1 may have anti-injury effect on regulating liver immune inflammatory injury. Based on the above findings, we generate the following hypothesis: Negative regulation of the TLR-IL-1R inflammatory signaling pathway by over-expressing SIGIRR and SOCS1 in both DC and T cells will control the immune response and inhibit allograft rejection. In this project, recipient rats will be transfected with adenovirus-SIGIRR and adenovirus-SOCS1 before allogeneic liver transplantation. The immune status will be evaluated in these transfected recipients post transplantation to confirm the effect of adenovirus-SIGIRR and adenovirus-SOCS1 transfection in inhibiting alloimmune responses. Molecules involved in TLR-IL-1R signaling pathway will be investigated in order to further understand the molecular mechanisms of transplantation tolerance induction in this setting. This project is designated to explore a new method to induce transplantation tolerance and investigate the underlying mechanisms, thus may provide scientific basis for a new approach to regulate immune responses in transplantation.

诱导免疫耐受是提高移植受者长期存活的重要手段。我们的前期研究通过干预共刺激信号的方法可延长移植物存活时间，但其远期仍最终被排斥和导致移植物失活。最新研究发现炎症反应的TLR-IL-1R通路可通过促进DC发育和Th细胞分化增殖，进而调控移植免疫反应。此通路受SIGIRR和SOCS1的负调控。我们预实验显示：SIGIRR和SOCS1过表达能够分别减轻内毒素诱导的气道上皮细胞株和急性肝损伤的炎症反应。由此我们提出假说：启动炎症信号通路的负调控机制影响DC成熟和Th细胞分化增殖，可达到干预免疫应答进而抑制移植排斥反应的目的。本课题拟采用已建立的大鼠肝移植模型，通过腺病毒载体将SIGIRR和SOCS1转染受体大鼠并使其高表达，观察其对肝移植免疫排斥的抑制作用，并探讨通过负调控TLR炎症通路而致移植耐受的分子机制。本课题旨在探索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科学依据

器官移植是目前治疗各类终末期疾病最有效的手段之一，诱导移植免疫耐受是提高移植受者长期存活的重要手段。近期研究发现炎症反应的TLR-IL-1R通路可通过促进DC发育和Th细胞分化增殖，进而调控移植免疫反应。此通路受SIGIRR和SOCS1的负调控。在本项目的研究中，我们采用已建立的大鼠肝移植模型，通过腺病毒载体将SIGIRR和SOCS1转染受体大鼠并使其高表达，观察其对肝移植免疫排斥的抑制作用，并探讨通过负调控TLR炎症通路而致移植耐受的分子机制。项目组发现启动炎症信号通路的负调控机制影响DC成熟和Th细胞分化增殖，可达到干预免疫应答进而抑制移植排斥反应的目的。我们的研究显示：SIGIRR基因能有效抑制未成熟DCs在LPS等外源刺激因子作用下的成熟和活化，抑制抗原提呈功能，在一定程度上延长移植物存活时间，诱导免疫保护形成。而且DC高表达SOCS1分子后展示出一定程度的未成熟属性，DC-SOCS1减少受体小鼠体内Th1及Tc1的淋巴细胞含量，DC-SOCS1诱导T细胞低反应性，SOCS1基因抑制DC成熟，诱导T细胞无能并对移植物起到免疫保护作用。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10篇（通讯作者），已获得授权的国家专利4项（均为第1发明人），并获得2015年国家科技奖（排名第5）。