Cell Interactions in the Inflamed Intestinal Mucosa

描述(申请人提供)：涉及多种单元格类型 慢性炎症反应的发生和持续。这种情况也会发生 在炎症性肠病(IBD)中，免疫功能长期激活 而非免疫细胞会导致严重的结构和功能异常。 在上一个资助期进行的研究已经确定了表型 和两种非免疫肠道细胞的功能特征， 人肠微血管内皮细胞与肠道 成纤维细胞(HIF)，并评估这些细胞与粘膜之间的相互作用 T细胞。结果表明，HIMEC和HIF都发挥了积极的作用 T细胞与细胞因子结合在免疫和炎症中的作用 制作。这些观察结果有力地支持了这样一个概念 免疫-非免疫细胞相互作用在发病机制中起着关键作用。 和IBD的持久性。然而，粘膜中细胞的相互作用需要 更好地了解，特别是在征聘机制方面 刺激局部非免疫细胞的T细胞。细胞间的通信是 由各种趋化、黏附和激活分子控制 直接运动、接触和刺激。这项提案将调查 HIMEC和HIF来源的T细胞募集的调控机制 趋化因子和这种效应的后果。CD40L在大肠杆菌中的表达 非免疫细胞激活的T细胞及其受体CD40是一种 研究细胞相互作用分子机制的理想系统 时尚。因此，我们将检验以下中心假设： CD40/CD40L系统控制T细胞-非免疫细胞的自我永续循环 导致IBD慢性化的相互作用。这一假设将是 测试有三个特定的目的：1)定义T细胞趋化因子的谱 由HIMEC和HIF产生；2)研究T细胞对 HIMEC和HIF衍生的趋化因子；3)鉴定受体-配体对并 T细胞诱导HIMEC和HIF趋化因子产生的信号通路。 阻断CD40或CD40L可能中断免疫-非免疫的慢性循环 在IBD中发生的细胞相互作用并导致临床益处，因为 由自身免疫和炎症的动物模型建议，包括 实验性IBD。

DESCRIPTION (provided by applicant): Multiple cell types are involved in the development and persistence of chronic inflammatory response. This also occurs in inflammatory bowel disease (IBD), where long-standing activation of immune and non-immune cells results in severe structural and functional abnormalities. Studies performed during the last funding period have defined the phenotypic and functional characteristics of two types of nonimmune intestinal cells, human intestinal microvascular endothelial cells (HIMEC) and intestinal fibroblasts (HIF), and assessed the interaction between these cells and mucosal T-cells. The results demonstrated that both HIMEC and HIF play an active role in immunity and inflammation through binding of T-cells and cytokine production. These observations strongly support the concept that immune-nonimmune cell interactions are critically involved in the pathogenesis and persistence of IBD. However, the interplay of cells in the mucosa needs to be better understood, particularly in regard to the mechanisms of recruitment of T-cells that stimulate local nonimmune cells. Cell-to-cell communication is controlled by a variety of chemotactic, adhesion and activation molecules that direct movement, contact and stimulation. This proposal will investigate the mechanisms regulating the recruitment of T-cells by HIMEC- and HIF-derived chemokines and the consequences of this effect. The expression of CD40L by activated T-cells and of its counter-receptor CD40 by nonimmune cells is an ideal system to study molecular mechanisms of cell interaction in an integrated fashion. Therefore, we will test the following central hypothesis: The CD40/CD40L system controls a self-perpetuating cycle of T-cell-nonimmune cell interactions that contribute to chronicity of IBD. This hypothesis will be tested by three specific aims: 1) Define the spectrum of T-cell chemokines produced by HIMEC and HIF; 2) Investigate T-cell chemotaxis in response to HIMEC- and HIF-derived chemokines; 3) Identify the receptor-ligand pairs and signaling pathways mediating T-cell-induced HIMEC and HIF chemokine production. Blockade of CD40 or CD40L may interrupt the chronic cycle of immune-nonimmune cell interactions occurring in IBD and result in clinical benefits, as suggested by animal models of autoimmunity and inflammation, including experimental IBD.