CD30L/CD30在IBD病变形成机制中的调节作用及其单抗的治疗效应。

Human inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by inflammation in the intestine associated with uncontrolled innate and adaptive immunity against normal constituents, but its pathogenesis is still unclear. Numerous studies have been demonstrated that various T cell subsets involved in the development and outcome of autoimmune diseases, including IBD. Recent studies have found that CD30 ligand (CD30L, CD153)/CD30 signaling, a member of TNF/TNFR superfamily, plays an important role in the regulation of helper T (Th) cell responses in vivo and in vitro. In this study, we plan to use CD30LKO or CD30KO mice to elucidate the mechanism of CD30L/CD30 signaling in controlling the intestinal T cell functional differentiation, especially the intracellular signal transduction pathway of CD30-CD30L reverse signaling regulates Th17 cell differentiation; to examine the critical role of CD30L/CD30 signaling in the pathogenesis of T cell-mediated intestinal inflammation; to explore the effect of CD30L/CD30 signaling on the maintenance and effector function of IL-17A+gamma-deltaT cells in the lamina propria of intestine; to investigate the interaction between IL-17A+gamma-deltaT cells and CD4+Th17 cells. And then, we plan to evaluate the effect of CD30L-reverse signaling targeted therapy in IBD. All of these works will make a huge contribution to develop the biotherapy for human IBD.

慢性炎症性肠病（IBD）发病机理仍不十分清楚。研究证明多种T细胞亚群参与该病的发生发展与转归。近来研究发现CD30L/CD30参与T细胞亚群的应答调节。为此，本项目拟利用CD30或CD30L基因敲除小鼠探讨：CD30-CD30L"反向信号"调节Th17细胞分化的细胞内传导通路；CD30L/CD30信号在T细胞介导的肠道炎症发病机制中的重要作用；CD30L/CD30信号对肠固有层IL-17A+gamma-deltaT细胞的维持及效应功能的影响；IL-17A+gamma-deltaT细胞与CD4+Th17细胞间的相互作用关系；观察针对CD30-CD30L"反向信号"靶向性治疗IBD的效果和应用价值。将为弄清CD30L/CD30信号系统在IBD的炎症发生发展中对肠道T细胞亚群的调控作用机制，及探索针对CD30-CD30L"反向信号"作用的靶向性IBD治疗提供科学依据和新思路。

目前慢性炎症性肠病（IBD）发病机理仍不十分清楚。研究证明多种T细胞亚群参与该病的发生发展与转归。近来我们研究发现CD30L/CD30参与T细胞亚群的应答调节。因此,在本项目利用CD30或CD30L基因敲除小鼠探讨了CD3OL/CD30信号对肠黏膜固有层γδ T细胞的维持及效应功能的影响。研究发现：1.CD30和CD30L可表达在肠固有层γδ T细胞；2. 与WT小鼠比较，CD30LKO或CD30KO小鼠肠固有层产生IL-17A的γδ T细胞明显减少，但产生IFN-γ的γδ T细胞无明显变化；3. commonγ chain细胞因子IL-7能够诱导肠固有层γδT细胞表达CD30L，并促进γδT细胞分泌IL-17A，且这一过程为CD30L依赖性；4.与正常γδT细胞相比， CD30L基因缺失小鼠γδT细胞移植能够明显降低T细胞移植诱导的免疫缺欠小鼠的炎症性肠疾病发病程度。本项目研究将为进一步弄清CD30L/CD30信号系统在IBD的炎症发生发展中对肠道T细胞亚群的调控作用机制，及探索针对CD30-CD30L"反向信号"作用的靶向性IBD治疗提供科学依据和新思路。