Dupilumab opens a therapeutic window in food protein-induced enterocolitis syndrome by unlicensing dendritic cells

Food-protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated reaction to food antigens for which no disease-modifying treatment exists. The mechanistic heterogeneity of FPIES-spanning multiple incompletely understood immune pathways-has hindered the prioritization of therapies in clinical trials.

In this observational study, we sought to determine whether dupilumab, an mAB that is an IL-4 receptor-alpha antagonist, can induce clinical remission in FPIES.

We describe (1) a detailed single-patient case of wheat-triggered, endoscopy-confirmed colitic FPIES treated with dupilumab 300 mg subcutaneously every 2 weeks and (2) a prospective follow-up of 7 additional patients with FPIES all of whom initiated dupilumab for FDA approved comorbidities as a part of their clinical care. Serial flow cytometry quantified dendritic-cell OX40-ligand (OX40L) and CD8⁺ chemoattractant receptor-homologous molecule positive T-cell subsets before and after treatment; open food challenges assessed clinical tolerance.

Index case: Within 2 injections of dupilumab, the wheat-sensitive patient tolerated a 50-g wheat protein challenge without gastrointestinal symptoms-first uneventful exposure in 20 years. Discontinuation of dupilumab led to relapse; reinitiation again restored clinical tolerance. OX40L⁺ dendritic cells (DCs) fell from 22% to 8% to 10% and remained stable, whereas circulating chemoattractant receptor-homologous molecule positive CD8 (T cytotoxic 2) cells increased to approximately 12%, suggesting redistribution of these T cells from the gut tissue. Cohort: All 7 additional patients (ages 2-58 years; triggers: milk, soy, rice, wheat, shellfish) achieved unrestricted dietary tolerance within 3 months, mirroring the immunophenotypic trajectory of the index case. All patients had provided consent under Western Institutional Review Board (protocol no. 20121950).

Dupilumab rapidly and durably abrogated food reactivity across diverse FPIES phenotypes associated with downregulated dendritic-cell OX40L. These findings identify the IL-4/IL-13-OX40L axis as a tractable therapeutic target and support formal trials of dupilumab-including high-dose "rescue" regimens-in acute and chronic FPIES.