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

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-4RαY709F 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 Il4raY709F 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. 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. 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. Skin-sensitized intestinal IL-9 transgenic (IL9Tg) and IL9Tg mice backcrossed onto the IL-4RαY709F 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. Subcutaneous sensitization and a single intragastric allergen challenge of egg antigen to BALB/c IL9Tg mice and Il4raY709F 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. 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.