TL1A参与炎症性肠病肠道黏膜免疫应答调节的研究

Although the precise etiologies of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), remain unclear, several reports have indicated that dysfunction of the mucosal immune system plays an important role in its pathogenesis. TNF-like cytokine 1A (TL1A，TNFSF15), is a member of the TNF superfamily and expressed on activated T cells, dendritic cells and monocytes. TL1A expression is enhanced in the intestinal mucosa of IBD patients. Thus, TL1A may participate in the pathogenesis of several inflammatory diseases, including IBD (CD and UC). However, the immunoregulatory mechanism of TL1A/death domain receptor 3 (DR3) pathway in pathogenesis of gut mucosal inflammation is still unclear. In this study, we will investigate the immunoregulatory role of TL1A in pathogenesis of IBD, using TL1A-knock out (TL1A-/-) mice. We plan to use wild type (WT) and TL1A-/- mice to induce several experimental colitis models, and TL1A or DR3 expression in the intestinal mucosa-associated lymphoid tissues of WT mice before/after development of intestinal inflammation will be determined, and measure the accumulation of inflammatory lymphocytes in mucosal, and examine the proliferation and differentiation of intestinal mucosal lamina propria T cells in vivo, including Th1, Th2, Th17 or Treg. Moreover, the immunoregulatory role of TL1A in modulation of Th cell differentiation in vitro will also be investigated, using agonistic or antagonistic anti-TL1A protein. Finally, experimental therapy with neutralizing anti-TL1A antibody in WT mice will also be performed to determine whether TL1A/DR3 signaling pathway really contributes to IBD pathogenesis, and whether modulation this signaling pathway by antibody could prevent intestinal mucosal inflammatory development. This work will clarify the potential role of TL1A in the pathogenesis of IBD and provide an important theoretical basis for IBD immune therapy.

炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC），其发病机制与肠黏膜免疫系统对肠道内菌群异常应答密切相关。TL1A(TNFSF15)是TNF超家族的新成员,其编码基因已被确定为IBD易感基因，IBD患者肠黏膜TL1A表达水平异常增高，揭示了TL1A在IBD发病机制中起重要作用。但TL1A对肠黏膜免疫调节机制尚不明确。为此，我们将重点利用TL1A-/-小鼠诱导不同类型的IBD模型，观测TL1A基因缺失对肠炎发生发展的直接影响；探讨TL1A在小鼠IBD模型病变形成中的免疫调节机制，分析在体内、外不同条件下TL1A/DR3间相互作用对T细胞分化的效应机制，评价调节TL1A/DR3 途径对小鼠炎症性肠病的治疗效果。本项目研究将首次利用TL1A基因敲除小鼠，详细阐述TL1A对肠黏膜免疫应答的调节机制，为针对临床IBD免疫生物学治疗法的开发与应用提供新的思路和重要的理论依据。

炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC），其发病机制与肠黏膜免疫系统对肠道内菌群异常应答密切相关。TL1A(TNFSF15)是TNF 超家族的新成员,其编码基因已被确定为IBD 易易感基因，IBD 患者肠黏膜TL1A 表达⽔水平异常增⾼高，提示了了TL1A在IBD 发病机制中可能发挥潜在的重要作⽤用。但TL1A 对肠黏膜免疫调节机制尚不不⼗十分明确。为此，本项⽬目研究利利⽤用TL1A基因敲除⼩小⿏鼠，诱导包括DSS、TNBS和OXA等多种⼩小⿏鼠不不同类型的肠炎模型，深⼊入探讨了了TNF超家族成员—TL1A通过调控肠道黏膜免疫应答，参与不不同类型肠道炎症病变形成的机制。研究结果发现：1）TL1A基因缺失可引起⼩小⿏鼠炎症性肠组织固有层内mDCs数量量明显减少，效应性/记忆性CD4+T细胞蓄积明显降低，⽽而效应性Treg细胞数量量及活化明显增强；2）TL1A基因缺失可引起⼩小⿏鼠炎症性肠组织固有层内Th1/Th17细胞应答被显著抑制，⽽而Th2和Treg细胞应答明显增强。综上所述，研究结果证明TL1A/DR3信号转导可通过调节肠固有层Th1/Th17/Treg细胞应答的平衡，抑制Treg细胞应答，促进Th1、Th17或Th1/Th17细胞分化及其相关细胞因⼦子的产⽣生，亦可通过促进mDCs的功能，上调肠固有层Th1和Th17细胞应答，相反下调Th2细胞应答，进⽽而在DSS和TNBS等诱导的“CD”肠炎模型中发挥重要的促炎作⽤用，⽽而相反在OXA诱导的“UC”肠炎模型中发挥潜在的抑炎作⽤用。本项⽬目研究结果可为TL1A/DR3信号通路路成为临床IBD免疫⽣生物学治疗的潜在新靶点提供重要的理理论基础和实验数据。