Role of the co-stimulator molecular SLAM in colitis

描述（由申请人提供）： 导致慢性炎症状态的活化T细胞的失调是炎性肠病（溃疡性结肠炎和克罗恩病）的中心特征。在活化的T细胞和抗原呈递细胞（即巨噬细胞和树突细胞）上表达的共刺激分子协调T细胞（抗原呈递细胞）相互作用并定义T细胞应答的类型（即活化与无反应性）。SLAM（signaling leukocytic activation molecule，CD 150）是一种在活化的T细胞和巨噬细胞上高度表达的共刺激分子。通过增加促炎细胞因子，SLAM共刺激增强炎症状态。初步数据表明，激活的T细胞上的SLAM信号传导的破坏保护免受结肠炎，并且SLAM缺陷（SLAM-/-）巨噬细胞在促炎功能中具有严重缺陷。基于这项工作，我们产生了新的假设，即SLAM共刺激对介导结肠炎慢性炎症的巨噬细胞和活化T细胞的功能至关重要。在具体目标#1中，我们将使用与Rag-/-背景（无T或B细胞）杂交的SLAM -/-小鼠来检验抗原呈递细胞上的SLAM表达对实验性结肠炎的诱导和维持至关重要的假设。在具体目标#2中，将研究SLAM-/- T细胞引起结肠炎的潜力。在具体目标#3中，将在两种实验性结肠炎模型中体内测试抗SLAM抗体预防结肠炎的能力。本研究将通过细胞因子测定（ELISA）在体外检测不同T细胞亚群和巨噬细胞的活化状态。将通过临床参数（即体重减轻、腹泻）以及尸检时结肠的组织学评分进行体内结肠炎评估。这项工作将确定SLAM在结肠炎的启动和维持中的作用，并有可能确定人类炎症性肠病免疫调节的新治疗靶点。

DESCRIPTION (provided by applicant): Dysregulation of activated T cells leading to a chronic inflammatory state is a central feature of inflammatory boweI disease (ulcerative colitis and Crohn's disease). Co-stimulatory molecules expressed on activated T cells and antigen presenting cells (i.e. macrophages and dendritic ceils) orchestrate T cell((antigen presenting cell interaction and define the type of T cell response (i.e. activation vs. anergy). SLAM (signaling leukocytic activation molecule, CD150) is a co-stimulatory molecule highly expressed on both activated T cells and macrophages. Through augmentation of pro-inflammatory cytokines, SLAM co-stimulation potentiates the inflammatory state. Preliminary data suggest that disruption of SLAM signaling on activated T cells protects against colitis and SLAM deficient (SLAM-/-) macrophages have a profound defect in pro-inflammatory function. Based on this work we generate the novel hypothesis that SLAM co-stimulation is critical to the function of both macrophages and activated T cells that mediate chronic inflammation in colitis. In specific aim #1, we will use SLAM -/- mice crossed to the Rag-/- background (no T or B cells) to test the hypothesis that SLAM expression on antigen presenting cells is critical to the induction and maintenance of experimental colitis. In specific aim #2, the potential of SLAM-/- T cells to cause colitis will be studied. The ability of anti-SLAM antibodies to prevent colitis will be tested in vivo in two models of experimental colitis in specific aim #3. The studies will test activation states of different T cell subsets and macrophages in vitro by cytokine assay (ELISA). Assessment of colitis in vivo will be made by clinical parameters (i.e. weight loss, diarrhea) as well as histologic scoring of the colon at autopsy. This work will establish the role for SLAM in the initiation and maintenance of colitis and has the potential of identifying a new therapeutic target for the immune modulation of human inflammatory bowel disease.