Modulation of intestinal inflammation in colitis by manipulating dendritic cells

描述（由申请人提供）：炎症性肠病（IBD）是慢性复发性炎症性疾病；其发病机制涉及的因素包括患者的遗传背景、肠道内共生菌或致病菌的作用以及先天和适应性免疫反应的异常激活。树突状细胞（dc）似乎在调节先天和适应性免疫反应中发挥作用。来自肠道固有层的树突状细胞通过模式识别受体（如toll样受体（TLRs））识别细菌成分并作出反应。tlr检测到一种独特的保守的微生物成分，所以总的来说，它们可以检测到大多数微生物。tlr被微生物的特定成分激活，如：FMLP、LPS、PG-PS、脂质体酸和某些宿主分子。一旦dc上的tlr识别细菌成分，dc就会作为抗原呈递细胞（APC），这是T细胞激活的关键介质。先前的研究表明，t细胞对凋亡的抵抗有助于炎症性肠病（IBDs）中不适当的t细胞积累和慢性粘膜炎症的持续。FasL和肿瘤坏死因子相关凋亡诱导配体（TRAIL）属于TNF超家族的一个亚群，它们通过结合其死亡结构域受体诱导细胞凋亡。凋亡诱导配体如FasL和TRAIL在细胞调控中起重要作用。FasL是一种II型跨膜蛋白，属于肿瘤坏死因子家族，在活化的脾细胞和胸腺细胞中表达，与其参与t细胞介导的反应一致。最近的研究表明，TRAIL还可能诱导多种组织细胞和白细胞的凋亡。该建议的中心假设是，通过FASL和TRAIL在dc上的表达介导，诱导活性CD4 T细胞凋亡，将对慢性IBD期间发生的特征性炎症具有治疗作用。本课题的具体目的是：1)在体外研究T细胞作为APC与DCs的相互作用；2)在体外研究FASL和TRAIL表达介导的活性CD4 T细胞凋亡对DCs的影响；3)确定结肠炎期间DCs中FASL和TRAIL表达介导的活性CD4 T细胞凋亡的影响。这些研究将有助于我们了解结肠炎的免疫机制，并为将来使用体外生成的dc作为恢复肠道免疫的治疗工具提供可能性。

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) are chronic relapsing inflammatory conditions; the factors involved in their pathogenesis include the genetic background of patients, the effect of commensal or pathogenic bacteria in the gut, and abnormal activation of innate and adaptive immune responses. Dendritic cells (DCs) appear to play a role in modulating both the innate and adaptive immune response. DCs from the lamina propia of the intestines recognize and respond to bacterial components using pattern recognition receptors, such as Toll-like receptors (TLRs). TLRs sense a distinct repertoire of conserved microbial components, so that collectively, they can detect most microbes. TLRs are activated by specific components of microbes, such as: FMLP, LPS, PG-PS, lipoteicoic acid and certain host molecules. Once TLRs on DCs recognize bacterial components, DCs act as antigen presenting cells (APC), which are critical mediators of T cell activation. Previous studies have shown that T-cell resistance against apoptosis contributes to inappropriate T-cell accumulation and the perpetuation of chronic mucosal inflammation in inflammatory bowel diseases (IBDs). FasL and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) belong to a subgroup of the TNF superfamily which induces apoptosis by binding to their death domain containing receptors. Apoptosis-inducing ligands such as FasL and TRAIL have been found to play an important role in cell regulation. FasL is a type II transmembrane protein that belongs to the tumor necrosis factor family and is expressed in activated splenocytes and thymocytes, consistent with its involvement in T-cell-mediated responses. Recent data indicate that TRAIL may also induce apoptosis in various tissue cells and leukocytes. The central hypothesis of this proposal is that inducing the apoptosis of active CD4 T cells, mediated by the expression of FASL and TRAIL on DCs, will have a therapeutic effect against the characteristic inflammation that occurs during chronic IBD. The specific aims of this proposal are to1) examine in vitro the interaction of T cells with DCs as an APC 2) to examine in vitro the effect of the apoptosis of active CD4 T-cells mediated by the expression of FASL and TRAIL on DCs 3) determine the effect of the apoptosis of active CD4 T-cells mediated by the expression of FASL and TRAIL in DCs during colitis. These studies will contribute to our understanding of the immune mechanisms that occur in colitis and to the possibility of using ex vivo-generated DCs as therapeutic tools for restoring intestinal immunity in the future.