ABSTRACT Eosinophilic Esophagitis (EoE) is an oral- and aero-antigen mediated allergic disease of increasing prevalence and incidence. EoE is characterized by esophageal fibrosis, rigidity, and smooth muscle hypertrophy, resulting in food impactions and strictures, vomiting, poor appetite, failure to thrive, and dysphagia. Chronic Th2-type inflammation of the esophagus in EoE can lead to fibrosis and other features of tissue remodeling that induce esophageal narrowing and associated food impactions 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. Our current lack of therapies that can halt or reverse EoE associated remodeling creates a pressing need for therapies since approximately 50% of patients have treatment resistant disease or inflammation that recurs despite ongoing therapy. In the first cycle of this grant, we demonstrated the presence of the TNF superfamily member, TNFSF14/LIGHT in all T cell subsets in the active EoE esophagus. Further, we demonstrated that esophagus fibroblasts were a major target of LIGHT, expressing both receptors (LTR and HVEM) for this cytokine. LIGHT induced differentiation of pathogenic and remodeling fibroblasts with increased pro-inflammatory gene transcription and the ability to interact with human eosinophils dependent on both its receptors. The role of LIGHT in EoE was also supported by studies in a robust murine EoE model where the absence of LIGHT protected from esophagus remodeling. New novel data from our labs suggests that the there is a complex and concerted action of several cytokines in the TNF superfamily in EoE that includes not only LIGHT but also TNFSF12/TWEAK. TWEAK and its receptor TNFRSF12A/Fn14 are induced in the active EoE esophagus. TWEAK and LIGHT induce both unique and overlapping inflammatory fibroblast transcriptional phenotypes with TWEAK having substantive effects on myofibroblasts. Based on our new data that LIGHT, TWEAK, IFN, and IL-13 are co-expressed in esophageal T cells, that LIGHT and TWEAK interact functionally with IFN and IL-13 to induce fibroblast inflammatory and remodeling gene expression, and that their receptors are expressed in esophageal tissue from EoE patients and co-expressed on esophageal fibroblasts, we propose to test the hypothesis that LIGHT, TWEAK, and their receptors orchestrate EoE remodeling by inducing pro- inflammatory and pro-remodeling fibroblasts. We utilize primary human esophageal cells, tissues, and biopsies, from normal and EoE patients, as well as murine models of allergic esophagitis with gene-deficient whole animal and fibroblast-specific Fn14 and LTR deficient mice. Pre-clinical therapeutic blocking strategies will inform the concerted action of TWEAK and LIGHT and their interactions with IL-13 and INF in EoE remodeling. These studies may lead ...