Ulcerative Colitis - Regulation of the IL-13 Receptor System

描述(申请人提供)：IL-13和IL-13受体途径的失调是溃疡性结肠炎(UC)最明显的细胞因子异常。这一发现的意义不仅在于观察到IL-13在体外对结肠上皮细胞施加的毒性，以及通过抗IL-13策略成功治疗小鼠恶唑酮结肠炎，还在于最近一项针对UC的β-干扰素试验结果显示，治疗后IL-13的产生显著减少，仅限于临床应答者。由于目前正在开发多种针对配体-受体-信号通路中不同点的IL-13活性的新疗法，识别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疗效来优化临床试验设计。这项建议的初步数据显示，在许多(但不是所有)活动期溃疡性结肠炎患者中，上皮细胞上皮细胞诱骗的IL13Ralpha2受体显著上调，固有层单核细胞过度产生IL-13，而健康对照组和活动期克罗恩病患者中没有这种情况。这些发现为UC的新的关键问题提供了创新：在活动期UC中，上皮细胞IL13RA2的表达是保护还是损害，IL-13产生的异质性是否与NKT和天然淋巴样细胞产生有关，以及UC是否存在基于IL-13表达的内型可以预测对IL-13靶向治疗的反应？利用原代肠道组织，测量受体表达的调节、IL-13信号和受体活性的方法，以及产生IL-13和表达IL-13受体的细胞的表型，可以在UC患者、克罗恩病和健康对照组的亚群之间进行比较。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疾病活动的不同层次之间和内部的作用部位和机制。这一结果将适用于其他黏膜炎症性疾病，如过敏性哮喘和嗜酸性食管炎，在这些疾病中，IL-13也会导致疾病，需要针对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.