Mechanisms of adverse gastrointestinal events during oral immunotherapy

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ABSTRACT This K23 award application requests support for the career development of Dr. Benjamin Wright, Assistant Professor in the Division of Allergy, Asthma and Clinical Immunology at Mayo Clinic Arizona. The candidate’s overall goal is to become an independent, clinician-investigator and improve the health of individuals with eosinophilic esophagitis (EoE) and food allergy through patient-oriented research. This award will provide the training and support needed to accomplish this goal. Specifically, this proposal will enable Dr. Wright to accomplish the following short-term career goals: (1) acquire training in methods and design of clinical studies and trials in food allergy; (2) develop skills in basic/translational research techniques; (3) develop professional skills necessary to lead a translational research team; and (4) gather preliminary data and biospecimens for a subsequent R01 application and establish an independent research program in food allergy and eosinophilic gastrointestinal disorders. Oral immunotherapy (OIT) is an emerging treatment for food allergy. Although most patients can be successfully desensitized with OIT, many develop gastrointestinal side effects including EoE. EoE is a chronic allergic condition associated with severe esophageal dysfunction. The specific goals of the research proposal are to examine the mechanisms underlying the gastrointestinal side effects of OIT and to develop a novel treatment strategy to prevent them. To accomplish this, we will perform a sub-study of a placebo-controlled trial in patients with milk allergy treated with milk OIT with or without dupilumab. During the trial, we will serially monitor eosinophilic inflammation, markers of esophageal barrier dysfunction, and immune responses in peripheral blood and in the esophagus. To support Dr. Wright’s career development, he will acquire skills in cellular immunology and complete a basic science internship focusing on cutting-edge proteomic analysis of clinical samples. In addition, he will complete formal didactic coursework in clinical research study design, biostatistics, and bioethics. Dr. Wright has assembled a mentoring committee comprised of international experts in food allergy, EoE, proteomics, eosinophil biology, and type 2 immunity uniquely suited to address the hypotheses set forth in this proposal and guide Dr. Wright’s career development. This proposal combines the strength of the research environment at Mayo Clinic and an ongoing collaboration with Stanford University that provides an ideal setting to pursue the aforementioned training and research goals. At the conclusion of this program, Dr. Wright will have the skillset and experience required to transition to independence and lead a translational research team. Successful completion of this project will likely provide a major and sustained impact on the care of patients with food allergy by providing critical insights into the pathogenesis of food allergy and EoE.