IBD DISEASE SUBGROUP STRATIFICATION

说明(项目摘要) 特定的基因改变和细胞操作已经被用于 生成表达一系列临床表型的动物模型 炎症的位置、类型和强度的变化，并反映了 临床表现的多样性与患者的临床表现相似 克罗恩、S病(CD)和溃疡性结肠炎(UC)。在测试的动物模型中 到目前为止，共生细菌和宿主/细菌的相互作用已被证明 在粘膜炎症反应中起关键作用。动物们带着 在不同环境中长大的相同的基因操作 炎症的强度和/或位置的变化。这些型号 产生一种主要的粘膜细胞因子谱，对特定的 细胞因子阻断。CD和UC中都已经证明了该标记 抗体可以用来定义临床表型。在UC中，表达 血清PANCA与更严重的结肠炎和高发病率的结肠炎有关 慢性膀胱炎。在与项目1和项目3的合作中，我们展示了 PancA和另一种标记抗体ASCA将Cd分层为 临床疾病行为和严重程度。定义的患者群体 这些标记抗体的类型和/或组合对 肿瘤坏死因子-α阻滞剂。我们最近的调查已经确定了候选人 细菌抗原，并证明了这些抗原能够刺激 一种免疫反应。3个抗原与PANCA交叉反应，1个被鉴定 通过RDA可以用来定义T细胞反应和相关的临床 表现形式。这个项目中的研究是基于这样一个假设： 抗体表达及其水平定义特定的粘膜细胞因子 剧目。标记性抗体有望与不同的 T细胞对已知交叉反应的不同共生细菌抗原的反应 用这些抗体。还预计免疫反应是 与UC和CD中特有的临床表现相关 细胞因子的操纵或细菌抗原负荷的降低将调节 由这些免疫反应定义的患者亚群中的炎症。我们会 在UC和CS的研究中验证这一假设。首先，我们将定义 标志物和细菌反应性抗原与T细胞增殖的关系 以及临床定义的患者亚群中的细胞因子分泌。在UC， 免疫反应与阴囊炎发生和预防的关系 被调查。在CD中，免疫细菌反应的能力可以定义 对Th1细胞因子抑制和/或管腔反应最好的患者 将对细菌的减少进行调查。

DESCRIPTION (Abstract of the Project) Specific genetic alterations and cellular manipulations have been used to generate animal models that express a range of clinical phenotypes with variations in location, type, and intensity of inflammation, and reflect a variety of clinical expressions similar to that seen among patients with Crohn?s disease (CD) and ulcerative colitis (UC). In the animal models tested thus far, commensal bacteria and host/bacterial interactions have been shown to play a critical role in the mucosal inflammatory response. Animals with the same genetic manipulation when raised in different environments manifest variations in the intensity and/or location of inflammation. These models produce a dominant mucosal cytokine profile that responds uniquely to specific cytokine blockade. It has been demonstrated in both CD and UC that marker antibodies can be used to define clinical phenotypes. In UC, the expression of serum pANCA is associated with more severe colitis and a high incidence of chronic pouchitis. In collaboration with Projects 1 and 3, we demonstrated that pANCA and another marker antibody, ASCA, stratify CD into phenotypes of clinical disease behavior and severity. The groups of patients defined by the type and/or combination of these marker antibodies have variable responses to TNF-alpha blockade. Our recent investigations have identified candidate bacterial antigens and demonstrated the ability of these antigens to stimulate an immune response. Three antigens cross-reacting with pANCA, and 1 identified by RDA can be used to define T-cell responses and associated clinical manifestations. Studies in this project are based on the hypothesis that marker antibody expression and level thereof define specific mucosal cytokine repertoires. Marker antibodies are expected to be associated with distinct T-cell responses to different commensal bacterial antigens known to cross-react with these antibodies. It is also expected that the immune responses are associated with characteristic clinical expressions within UC and CD and that cytokine manipulation or diminution of bacterial antigenic load will regulate inflammation in subsets of patients defined by these immune responses. We will test this hypothesis in studies of UC and CS. First, we will define the relationship of marker and bacteria reactive antigens to T cell proliferation and cytokine secretion in clinically defined subsets of patients. In UC, the relationship of immune response to development and prevention of pouchitis will be investigated. In CD, the ability of immune bacterial response to define patients who will respond best to Th1 cytokine inhibition and/or lumenal bacterial diminution will be investigated.