Role of the co-stimulator molecular SLAM in colitis

描述(由申请人提供)： 激活的T细胞调节失调导致慢性炎症状态是炎症性肠病(溃疡性结肠炎和克罗恩病)的主要特征。在活化的T细胞和抗原提呈细胞(即巨噬细胞和树突状细胞)上表达的共刺激分子协调T细胞(抗原提呈细胞)相互作用，并定义T细胞反应的类型(即激活与无能)。SLAM是一种共刺激分子，在活化的T细胞和巨噬细胞上高度表达。通过增强促炎细胞因子，SLAM共刺激增强了炎症状态。初步数据表明，破坏激活的T细胞上的SLAM信号可以预防结肠炎，SLAM缺陷(SLAM-/-)巨噬细胞在促炎功能方面存在严重缺陷。基于这项工作，我们产生了一个新的假设，即SLAM共刺激对巨噬细胞和激活的T细胞的功能至关重要，巨噬细胞和激活的T细胞介导结肠炎的慢性炎症。在特定的目标1中，我们将使用与RAG-/-背景(没有T或B细胞)杂交的SLAM-/-小鼠来检验这一假设，即SLAM在抗原提呈细胞上的表达对于实验性结肠炎的诱导和维持至关重要。在具体目标#2中，将研究SLAM-/-T细胞引起结肠炎的可能性。抗SLAM抗体预防结肠炎的能力将在体内针对特定目标#3的两种实验性结肠炎模型进行测试。该研究将通过细胞因子分析(ELISA)在体外测试不同T细胞亚群和巨噬细胞的激活状态。活体结肠炎的评估将通过临床参数(如体重减轻、腹泻)以及尸检时结肠的组织学评分来进行。这项工作将确立SLAM在结肠炎的发生和维持中的作用，并有可能为人类炎症性肠病的免疫调节寻找新的治疗靶点。

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.