# TWEAK/TNFSF12 and LIGHT/TNFSF14 interactions in allergic esophagitis remodeling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $745,047

## Abstract

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 (LTR 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 LTR 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 ...

## Key facts

- **NIH application ID:** 10818248
- **Project number:** 2R01DK114457-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Seema S Aceves
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $745,047
- **Award type:** 2
- **Project period:** 2018-04-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818248

## Citation

> US National Institutes of Health, RePORTER application 10818248, TWEAK/TNFSF12 and LIGHT/TNFSF14 interactions in allergic esophagitis remodeling (2R01DK114457-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10818248. Licensed CC0.

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