Oral tolerance to foods normally develops during the first few years of life. An aberration of oral tolerance, food allergy, occurs in 6% of children and 3.5% of adults in the United States. Egg and peanut allergy are two of the most common food allergies occurring in 1.5% and 1% of young children, respectively. Interestingly, approximately 50% of young children with egg allergy then develop oral tolerance to egg by age 5 years, while only 20% of young children develop oral tolerance to peanuts by age 5 years. We propose to utilize a form of treatment, oral immunotherapy (OIT) to investigate and possibly hasten the development of oral tolerance to eggs and peanuts. This application is based on our data that allergen-specific OIT will desensitize and possibly tolerize egg-allergic and peanut-allergic subjects. Our hypothesis is that instituting egg and peanut OIT early after development of egg or peanut allergy will clinically desensitize both groups of patients by altering basophil/mast cell reactivity and will cause clinical tolerance to develop because of the activity of specific T regulatory cells for egg and peanut. This study will provide new insights into the natural history of the egg- and peanut-specific cellular and humoral immune responses and oral tolerance. This proposal is based on our preliminary studies that have examined the effects of OIT on egg and peanut allergies. Our approach will be to enroll two cohorts of subjects and controls early in life who have egg allergy or peanut allergy both soon after their development and treat them with either egg or peanut OIT in a randomized, blinded OIT protocol. Utilizing an already established protocol of study subjects entering a proof of concept study funded by the Food Allergy Project, we will study the basophil/mast cell reactivity, antigen-specific T cell responses and mucosal and systemic humoral immune responses in these subjects. This grant application is not intended to support the clinical trial portion of this work but only the mechanistic studies as described.
Our specific aims are the following: (1) determine if the development of the desensitized state to egg and peanut is associated with the down-regulation of mast cells and basophils, (2) determine if the development of clinical tolerance to egg and peanuts is associated with an increase in the T regulatory phenotype of antigen-activated peripheral CD4+ T cells and (3) determine the effect of egg- and peanut-specific mucosal and systemic humoral immune responses on oral tolerance and OIT. The short-term goal of the protocol is to induce a desensitized state to egg and peanut early in the course of treatment that will protect subjects from allergic reactions following accidental egg or peanut ingestions. The long-term goal of the study is to utilize egg and peanut OIT for the induction of clinical and immunologic tolerance to the allergen that will be sustained once the protocol is completed.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IMM-B (02))
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Minnicozzi, Michael
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Duke University
Schools of Medicine
United States
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Virkud, Yamini V; Burks, A Wesley; Steele, Pamela H et al. (2017) Novel baseline predictors of adverse events during oral immunotherapy in children with peanut allergy. J Allergy Clin Immunol 139:882-888.e5
Berglund, Jelena P; Szczepanski, Nicole; Penumarti, Anusha et al. (2017) Preparation and Analysis of Peanut Flour Used in Oral Immunotherapy Clinical Trials. J Allergy Clin Immunol Pract 5:1098-1104
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Ang, W X Gladys; Church, Alison M; Kulis, Mike et al. (2016) Mast cell desensitization inhibits calcium flux and aberrantly remodels actin. J Clin Invest 126:4103-4118
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Vickery, Brian P; Scurlock, Amy M; Kulis, Michael et al. (2014) Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J Allergy Clin Immunol 133:468-75
Chin, Stacy J; Vickery, Brian P; Kulis, Michael D et al. (2013) Sublingual versus oral immunotherapy for peanut-allergic children: a retrospective comparison. J Allergy Clin Immunol 132:476-8.e2
Bird, J Andrew; Kulis, Michael; Burk, Caitlin M et al. (2012) Tree nut- and sesame-specific IgE do not decrease from baseline with peanut oral immunotherapy (OIT). Ann Allergy Asthma Immunol 109:470-1
Vickery, Brian P; Scurlock, Amy M; Jones, Stacie M et al. (2011) Mechanisms of immune tolerance relevant to food allergy. J Allergy Clin Immunol 127:576-84; quiz 585-6
Vickery, Brian P; Chin, Stacy; Burks, A Wesley (2011) Pathophysiology of food allergy. Pediatr Clin North Am 58:363-76, ix-x

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