IL-4 receptor alpha signaling alters oral food challenge and immunotherapy outcomes in mice

Varsha Ganesan; Ankit Sharma; Sunil Tomar; Charles F Schuler 4th; Simon P Hogan

doi:10.1016/j.jaci.2022.07.011

IL-4 receptor alpha signaling alters oral food challenge and immunotherapy outcomes in mice

J Allergy Clin Immunol. 2023 Jan;151(1):182-191.e6. doi: 10.1016/j.jaci.2022.07.011. Epub 2022 Aug 4.

Authors

Varsha Ganesan¹, Ankit Sharma¹, Sunil Tomar¹, Charles F Schuler 4th², Simon P Hogan³

Affiliations

¹ Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich.
² Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich; Division of Allergy and Immunology, University of Michigan, Ann Arbor, Mich.
³ Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Mich; Department of Pathology, Michigan Medicine, University of Michigan, Ann Arbor, Mich. Electronic address: sihogan@med.umich.edu.

PMID: 35934083
DOI: 10.1016/j.jaci.2022.07.011

Abstract

Background: Food allergy diagnosis and management causes a number of social and emotional challenges for individuals with food allergies and their caregivers. This has led to increased interest in developing approaches to accurately predict food allergy diagnosis, severity of food allergic reactions, and treatment outcomes. However, the utility of these approaches is somewhat conflicting.

Objective: We sought to develop and utilize a murine model that mimics the disease course of food allergy diagnosis and treatment in humans and to identify biomarkers that predict reactivity during food challenge (FC) and responsiveness during oral immunotherapy (OIT) and how these outcomes are modified by genetics.

Methods: Skin-sensitized intestinal IL-9 transgenic (IL9Tg) and IL9Tg mice backcrossed onto the IL-4Rα^Y709F background received a single intragastric exposure of egg antigen (ovalbumin), underwent oral FC and OIT; food allergy severity, mast cell activation, and ovalbumin-specific IgE levels were examined to determine the predictability of these outcomes in determining reactivity and treatment outcomes.

Results: Subcutaneous sensitization and a single intragastric allergen challenge of egg antigen to BALB/c IL9Tg mice and Il4ra^Y709F IL9Tg induced a food allergic reaction. Enhanced IL-4Rα signaling altered the symptoms induced by the first oral exposure, decreased the cumulative antigen dose, increased the severity of reaction during oral FC, and altered the frequency of adverse events and OIT outcomes. Biomarkers after first oral exposure indicated that only the severity of the initial reaction significantly correlated with cumulative dose of oral FC.

Conclusion: Collectively, these data indicate that single nucleotide polymorphisms in IL-4Rα can alter clinical symptoms of food allergic reactions, severity, and reactive dose during FC and OIT, and that severity of first reaction can predict the likelihood of reaction during FC in mice with IL-4Rα gain of function.

Keywords: IL-4Rα gain of function; biomarkers; food challenge; genetics; oral immunotherapy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Administration, Oral
Allergens*
Animals
Biomarkers
Desensitization, Immunologic
Food Hypersensitivity*
Humans
Immunotherapy
Mice
Mice, Transgenic
Ovalbumin

Substances

Ovalbumin
Allergens
Biomarkers

Grants and funding

R01 AI112626/AI/NIAID NIH HHS/United States