Chronic inflammation of the gastrointestinal mucosa can lead to fibrosis and other features of tissue remodeling that limit normal functioning of the gastrointestinal tract. This is particularly apparent in patients with Eosinophilic Esophagitis (EoE), an oral- and aero-antigen mediated allergic disease of increasing prevalence and incidence. EoE is characterized by esophageal fibrosis and rigidity, and smooth muscle dysmotility, resulting in food impactions and strictures, vomiting, poor appetite, failure to thrive, and dysphagia. Current EoE treatments include antigen elimination diets and topical corticosteroids that can limit inflammation, but these measures may not control disease long term or reverse the course of esophageal remodeling and dysfunction. Although several inflammatory mediators are thought to contribute to inflammation in the esophagus, specifically IL-5, IL-13, and TGFb, it is of great importance to extend our understanding of proteins that drive fibrosis and remodeling in EoE, in order to define new potential targets for therapeutic intervention. We have previously found that members of the tumor necrosis factor (TNF) superfamily, namely LIGHT (TNFSF14) interacting with its two receptors HVEM (TNFRSF14) and LTbR (TNFRSF3), promote tissue remodeling in the lungs and skin driven by allergens in models of severe asthma and atopic dermatitis. Based on novel preliminary data that LIGHT, HVEM, and LTbR are over-expressed in esophageal tissue from active EoE patients; that HVEM and LTbR are expressed in esophageal epithelial cells and fibroblasts and their expression correlates with inflammatory mediators characteristic of EoE; that recombinant LIGHT is sufficient to induce EoE-like remodeling features in the mouse esophagus; and that LIGHT-deficient mice are protected from EoE-like disease induced by allergen, we propose to test the central hypothesis that LIGHT and its receptors are pivotal mediators and drivers of allergic esophagus fibrosis and remodeling. In this multi-PI application, we combine the expertise of Michael Croft (LJI and UCSD) who discovered the tissue remodeling activities of LIGHT and Seema Aceves (UCSD) who demonstrated the presence and potential mechanisms of esophageal remodeling in pediatric EoE subjects, with our co-investigator Richard Kurten (ACRI), an expert in human ex vivo model systems in allergic diseases. We will utilize primary human esophageal EoE and normal cells, tissues, and biopsies, as well as murine models of allergic esophagitis, in order to dissect the roles of LIGHT in EoE pathogenesis. These studies will help unravel the mechanisms of esophageal tissue remodeling, and have the potential for rapid clinical translation since LIGHT blocking antibodies are available for therapeutic use.
Remodeling of the esophagus is a serious issue driven by a variety of food- and aero-allergens that affects the well being of up to 1 in 1000 people and with an estimated healthcare cost of $1 billion. Defining proteins that drive or contribute to esophagus remodeling, fibrosis, and esophageal smooth muscle dysmotility, may lead to new treatment options for these patients. This proposal will test the hypothesis that the extracellular protein LIGHT/TNFSF14, produced by cells of the immune system, promotes structural changes in the esophagus that results in rigidity, dysmotility, food impactions and strictures, leading to general issues with swallowing and food consumption.
