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.
Interleukin-13 is a helminth-infection cytokine gaining prominence in modern diseases such as allergic asthma, ulcerative colitis and eosinophilic esophagitis. This project will define the variable role IL-13 plays in apparently uniform disease activity in UC by identifying the IL-13-producing cells and the pathways of IL- 13 action that are most important in the inflammation causing ulcerative colitis. These results will help predict the best new anit-IL-13 drug for testing in specific ulcerative colitis patients for maximum success.
|Fuss, Ivan J; Joshi, Bharat; Yang, Zhiqiong et al. (2014) IL-13R*2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis. Gut :|