TOB1对炎症性肠病肠黏膜组织内Th1/Th17细胞激活的免疫调节机制研究

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is characterized by chronic inflammation in the intestinal tract. The pathogenesis is unclear. Th1/Th17 cells have been implicated as playing key roles in the development of IBD. TOB1 is a member of the TOB/BTG anti proliferative (APRO) family of proteins, and widely expressed in CD4+ T. Although TOB1 plays a essential role in Th17 cell-related inflammatory disorders, it is still unclear in IBD. Our preliminary work indicated that the expression of TOB1 decreased obviously in peripheral blood mononuclear cell (PBMC) and intestinal mucosal inflammation tissue in IBD patients and acute colitis models of WT mice induced by TNBS. And up-regulation of TOB1 expression in CD4+ T cells inhibited Th1/Th17 cell proliferation and differentiation. Thus, we hypothesize that TOB1 may be involved in mechanism of T cell immune response in intestinal mucosa. In this study, we will establish acute and chronic colitis models of TOB1-/- mice and WT mice, to explore the immune mechanism of TOB1 in Th1/Th17 cell proliferation and differentiation in the pathogenesis of IBD, and provide an important theoretical basis for IBD immune therapy.

炎症性肠病（Inflammatory bowel disease，IBD）是与机体免疫系统密切相关的一种慢性炎症性疾病，其病理机制并不完全清楚。Th1/Th17细胞对IBD发生发展起关键作用。TOB1属于TOB/BTG抗增殖蛋白家族的一员，表达在CD4+ T细胞，对Th17细胞介导的免疫性疾病起重要调节作用，但在IBD中的作用并不清楚。我们前期研究发现IBD患者和实验性结肠炎模型小鼠的PBMC和肠黏膜炎症组织TOB1表达下降，通过细胞转染上调CD4+ T细胞中TOB1表达可明显抑制Th1/Th17细胞的增殖分化。由此提出TOB1可能参与了IBD肠黏膜T细胞的增殖分化效应。本研究将建立TOB1-/-小鼠与WT小鼠急慢性结肠炎模型，重点研究TOB1对肠黏膜炎症的发生尤其是对Th1/Th17细胞增殖分化的免疫调节机制，阐明其对IBD发生发展的具体作用，为临床治疗IBD提供新的理论基础和分子靶点。

炎症性肠病（Inflammatory bowel disease，IBD）是一种反复复发、不可治愈的慢性炎症性疾病，其病理机制并不清楚。Th1/Th17细胞在IBD发生发展中起关键的作用。TOB1属于TOB/BTG抗增殖蛋白家族的一员，在CD4+ T细胞中高表达，对T细胞介导的免疫性疾病起重要调节作用。但TOB1在IBD病理机制中的作用并不清楚。我们研究发现TOB1在活动性IBD患者的肠黏膜炎症组织较正常组织明显降低，后续我们结合RNA-seq分析探索，通过体外细胞培养转染实验和小鼠肠炎模型体内实验，证实了TOB1通过Smad4/5-ID2的反应通路来抑制Th1/Th17所介导的免疫反应，从而抑制IBD的肠黏膜炎症的发展。该研究将为临床上IBD 的治疗提供新的理论基础和分子靶点。