可溶性糖蛋白sgp130通过阻断IL-6/sIL-6R跨信号通路诱导移植免疫耐受的实验研究

炎性细胞因子IL-6在移植排斥和耐受中发挥重要的作用。IL-6和细胞膜表面的IL-6R以及糖蛋白gp130结合激活经典信号通路，发挥抗炎及促进细胞再生的作用。而IL-6与可溶性IL-6受体（sIL-6R）及gp130结合激活跨信号通路，促进炎症反应，激活免疫系统，影响T细胞分化。前期研究结果证实完全阻断IL-6的作用能够诱导免疫耐受。抗IL-6抗体及IL-6R抗体不仅阻断了促炎的跨信号通路，同时也阻断了抗炎的经典信号通路。可溶性糖蛋白sgp130能够与IL-6/sIL-6复合物相结合，拮抗膜表面gp130，特异性地阻断跨信号通路，理论上是诱导免疫耐受更为理想的靶点。本课题拟从体外和体内两个方面研究sgp130对移植免疫的作用：（1）体外研究sgp130对同种异体抗原刺激的淋巴细胞增殖、分化以及细胞因子表达的影响；（2）利用小鼠心脏移植模型，在体内研究sgp130对移植免疫反应的影响及机理。

The proinflammatory cytokine IL-6 plays an important role in transplant rejection and tolerance induction. IL-6 combined with IL-6R and membrane gp130 activates classical signaling pathway,which can inhibit inflammation and promote cell regeneration.By contrast, IL-6 combined with soluble IL-6R and membrane gp130 activates trans-signaling pathway which can promote inflammation and activate the immune system.Previous studies have shown that completely blocking IL-6 can induce allograft tolerance in a mice cardiac transplantation model. IL-6 antibodies and IL-6R antibodies can block both proinflammatory and anti-inflammatory pathways. Soluble gp130 (sgp130) is a naturally occurring glycoprotein which can be found in plasma. Sgp130 acts as a antagonist of membrane gp130, which can bind IL-6 and soluble IL-6R. Sgp130 can specifically block the trans-signaling pathway, thereby making it a ideal target for IL-6 blocking during the tolerance induction. This project is to investigate the role of sgp130 in allo-immune responses both in vitro and in vivo. The first part is to determine the in role of sgp130 in vitro in T cell proliferation and differentiation as well as cytokine profile during the allo-antigen stimulate.The second part is to determine the in role of sgp130 in vivo in immune response and the underlying mechanism.