Ulcerative Colitis - Regulation of the IL-13 Receptor System

描述（由申请方提供）：IL-13和IL-13受体通路的失调是溃疡性结肠炎（UC）最明显的细胞因子异常。这一发现的重要性不仅通过观察到的IL-13对结肠上皮的体外毒性和通过抗IL-13策略成功治疗鼠恶唑酮结肠炎来确定，而且还通过最近在UC中进行的干扰素-β试验的结果来确定，该试验显示治疗后IL-13产生显著降低，仅限于临床应答者。由于目前正在开发多种靶向IL-13在配体-受体-信号传导通路中不同点的活性的新型疗法，因此确定UC中IL-13受体系统失调的主要机制将通过选择药物和监测效果来优化临床试验设计。 该提议的初步数据显示，在许多但不是所有的活动性溃疡性结肠炎患者中，上皮中诱饵IL 13 Ra 2受体显著上调，固有层单核细胞过量产生IL-13，而在健康对照和活动性克罗恩病中不存在。这些发现为有关UC的新的关键问题提供了创新：上皮IL 13 Ra 2表达对活动性UC具有保护作用还是有害作用，IL-13产生的异质性是否与NKT相对于先天淋巴细胞产生有关，以及是否存在基于IL-13表达的UC内型可以预测对IL-13靶向治疗的反应？使用原代肠组织，测量受体表达、IL-13信号传导和受体活性的调节以及产生IL-13和表达IL-13受体的细胞的表型的方法将允许在UC患者、克罗恩病和健康对照的亚组之间进行比较。这些研究将确定UC中IL-13的相关细胞来源、其产生的调节以及UC疾病活动不同层次之间和内部的作用部位和机制。这些结果将适用于其他粘膜炎性疾病，如过敏性哮喘和嗜酸性粒细胞性食管炎，其中IL-13也驱动疾病，需要靶向IL-13的新疗法。

DESCRIPTION (provided by applicant): Dysregulation of IL-13 and the IL-13 receptor pathway is the most defining cytokine abnormality of ulcerative colitis (UC). The significance of this finding is established not only by the observed toxicity exerted by IL-13 on the colonic epithelium in vitro and the successful treatment of murine oxazalone colitis by anti-IL-13 strategies, but also by results of a recent trial of interferon-beta in UC that showed significant post-treatment decreases in IL-13 production that were restricted to the clinical responders. Because multiple novel therapies targeting IL-13 activity at various points in the ligand-receptor-signaling pathway are currently in development, identifying the predominant mechanism of dysregulation of the IL-13 receptor system in UC will lead to optimized clinical trial design through choice of agent and monitoring for effect. The preliminary data for this proposal show striking upregulation of the decoy IL13Ralpha2 receptor in the epithelium and excess production of IL-13 by lamina propria mononuclear cells in many, but not all, active ulcerative colitis patients and are absent in healthy controls and active Crohn's disease. These findings provide the innovation for new and critical questions about UC: is the epithelial IL13Ra2 expression protective or injurious in active UC, is the heterogeneity of IL-13 production related to NKT versus innate lymphoid cell production, and are there IL-13 expression-based endotypes of UC that can predict response to IL-13-targeted therapies? Using primary gut tissue, methods to measure regulation of receptor expression, IL-13 signaling and receptor activity, and phenotypes of the cells producing IL-13 and expressing IL-13 receptors will allow comparison between subsets of UC patients, Crohn's and healthy controls. These studies will define the relevant cell source of IL-13 in UC, the regulation of its production and the sites and mechanisms of action among and within different strata of UC disease activity. The results will be applicable to other mucosal inflammatory diseases like allergic asthma and eosinophilic esophagitis where IL-13 also drives disease and new therapies targeting IL-13 are needed.