Basophil phenotype and activation in multi-food allergy and oral immunotherapy

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PROJECT SUMMARY Food allergy (FA) is a potentially fatal disorder in need of improved methods for diagnosis, clinical monitoring, and treatment. Basophils, the least common of the blood granulocytes, have been implicated as important contributors to the pathology of FA and food-induced anaphylaxis. Certain cell surface phenotypic features can help to identify basophils which have been activated by allergic mechanisms in vivo or in vitro. In this project, we will determine whether phenotypic and functional features of blood basophils can be used as part of an approach to predict the severity of clinical reactivity to food allergens in people with FA induced by multiple foods (herein: multi-FA), to improve the safety and efficacy of oral immunotherapy (OIT) protocols to treat FA, and, in principle, to customize immunotherapy protocols for each individual food allergic person. In Aim 1, we will perform detailed immunophenotyping to monitor the phenotype(s) and activation status of basophils and their subpopulations in the blood of participants with multi-FA, as measured ex vivo at baseline (defined herein as without ex vivo stimulation with allergens or anti-IgE). Blood will be obtained before the patients’ enrollment in a pilot, mechanistic-focused, phase 2 clinical trial of multi-OIT (defined as simultaneous OIT with multiple food allergens) conducted with or without omalizumab or dupilumab and at multiple intervals during the course of and after the end of such immunotherapy (IT) (see Project 1); we also will analyze blood from multi-FA participants not treated with OIT, atopic people without FA, and healthy non-atopic controls. This work will test the hypotheses: 1) that the expression of activation and/or other markers in blood basophils of multi-FA patients at baseline, before the cells’ ex vivo stimulation, correlates with the patients’ acute clinical reactivity to food allergens before and during IT and can be used to monitor the development and durability of desensitization and/or sustained unresponsiveness/“tolerance” induced by IT. In Aim 2, we will perform in vitro studies of basophil phenotype and function (i.e., basophil activation tests [BATs]), to measure basophil responses to challenge with food allergens ex vivo. This work will test the hypothesis that, in multi-FA patients, the magnitude of changes in basophil phenotype (e.g., expression of activation markers) and/or function (e.g., secretion of mediators) induced by challenge of their basophils with food allergens ex vivo correlates with the reduction in clinical evidence of food allergen sensitivity during IT and may also correlate with clinical outcomes of desensitization vs. sustained unresponsiveness/“tolerance”. One of our key long term goals is to develop innovative, rapid, and reliable methods to monitor basophil phenotype and function that can be used clinically for such purposes as predicting a person’s clinical sensitivity to food allergens, predicting the clinical outcome of OIT, customizing OIT and other IT protocols for individual people, and/or monitoring the development, effectiveness, or durability of immunotherapy.