Food allergies have become a world-wide public health problem, and allergy to peanuts is particularly problematic. In the U.S., ingestion of offending food allergens is the single most common cause of anaphylaxis seen in hospital emergency departments, and it is estimated that about 30,000 food-induced anaphylactic events are seen in U.S. emergency departments each year;sadly, about 200 of these events prove fatal. Either peanuts or tree nuts cause the majority of these deaths, and a recent survey in the U.S. found that 1.4% of the population is allergic to peanuts or tree nuts. Prior trials of immune desensitization using traditional and rush allergen protocols in patients with peanut allergy (PA) have shown partial rates of response but, unfortunately, have resulted in high rates of adverse reactions, including anaphylaxis. Recently, landmark studies by Dr. A. Wesley Burks and colleagues have shown success in desensitizing peanut-allergic children to peanut via an oral immunotherapy (OIT) protocol. The Stanford Alliance for Food Allergy Research (SAFAR, pronounced """"""""safer"""""""") is a multidisciplinary group whose goals are: 1) to develop and exploit state-of-the-art analytical methods, including advances in human immune monitoring, to improve understanding of the immune responses that give rise to food allergies and that underlie promising new approaches to treat this disorder, and 2) to contribute to the development and testing of improved approaches to diagnose, monitor, and treat subjects with food allergies. In this U19 application, we propose to conduct a large placebo-controlled, randomized, Phase 2 clinical trial of OIT in children and adults with PA and to measure a broad range of cellular, serologic, and clinical findings in longitudinal samples from PA patients undergoing the trial, as well as from appropriate control subjects (namely, groups of placebo-treated PA subjects, healthy controls, and atopic controls without PA). These data will be used to determine how key immune system parameters are altered during OIT, and which are most predictive of the nature and durability of patient responses to this therapy. In addition, we seek to define immune monitoring parameters, including findings derived from analyses of basophil phenotype and function that can be rapidly performed in a clinical laboratory using very small amounts of blood, that could be used to predict the clinical reactivity to peanut in PA subjects, to improve the safety and efficacy of OIT protocols, and/or to tailor the OIT protocol to each individual subject. We hope that such work will help to achieve the goal of devising a safe and effective curative treatment of this severe disorder.

Public Health Relevance

Peanut allergy (PA) is an increasingly common disorder which can cause serious illness and death in children and adults. We will use Innovative approaches for DNA sequencing, immune monitoring, and data analysis to investigate factors responsible for PA and to improve our ability to manipulate the immune system to cure subjects of PA. We will also try to develop rapid blood tests that can be used to tailor treatment for each individual patient with PA in order to improve the safety and efficacy of such treatment. Project 1: Induction of non-tolerance vs. tolerance in children and adults with peanut allergy Project Leader (PL): Nadeau, Kari DESCRIPTION (as provided by applicant): Peanut allergy (PA) is a severe form of food allergy for which improved treatments are needed. However, few studies have been conducted to optimize the safety of oral immunotherapy (OIT) for PA, to tailor OIT protocols according to the needs of individual PA patients, or to identify the immunological mechanism(s) underlying any long-lasting effects of oral immunotherapy (OIT) in such subjects. Specifically, it is not yet clear what factors will determine, in individual subjects, whether OIT induces tolerance (in which no set daily use of that food allergen is needed to allow for its safe consumption). To address these challenges, the Stanford Alliance for Food Allergy Research (SAFAR) plans to link the findings of the Phase 2 clinical study proposed here in Project 1 with the results of each of the other three projects of the U19 proposal focused on mechanistic studies (Projects 2, 3 &4), as well as with the results of the immune metrics assays carried out by Scientific Core B. Each of these projects and Core B will use patient samples from Project 1 collected at screening and longitudinally throughout the clinical study to integrate all data. We propose three main goals of our research for Project 1:
Specific Aim 1 : Test whether treatment of PA patients with OIT allows tolerance to be achieved (i.e., allows the subject to stop maintenance ingestion of peanut [during an """"""""avoidance period""""""""] for three months or more but then still undergo a successful double-blind placebo-controlled food challenge [DBPCFC] with peanut).
Specific Aim 2 : Determine whether treatment with our OIT protocol is safe in children and adults with peanut allergy (PA).
Specific Aim 3 : Evaluate to what degree current laboratory and clinical testing methods are associated with safety and tolerance outcomes (as identified in Specific Aims 1 and 2) in subjects with PA. By pursuing these aims, we will both: 1) provide the clinical samples, and the clinical outcome data, that will permit the innovative immune monitoring and mechanistic studies proposed in this U19 application to be accomplished, and 2) determine whether performing such immune monitoring has the potential to permit Individualization and optimization of safe and efficacious OIT protocols for individual PA patients.

Public Health Relevance

Food allergy is an important disease of children and adults that is in need of improved therapy. We propose a study to test whether adult and pediatric patients with one of the most dangerous food allergies, peanut allergy, can become tolerant to peanuts after an oral immunotherapy regimen so that they may be able to eat peanut safely.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI104209-02
Application #
8605841
Study Section
Special Emphasis Panel (ZAI1-PA-I (J1))
Program Officer
Dong, Gang
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$1,722,425
Indirect Cost
$625,339
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Boyd, Scott Dexter; Hoh, Ramona Amy; Nadeau, Kari Christine et al. (2017) Immune monitoring for precision medicine in allergy and asthma. Curr Opin Immunol 48:82-91
Andorf, Sandra; Manohar, Monali; Dominguez, Tina et al. (2017) Observational long-term follow-up study of rapid food oral immunotherapy with omalizumab. Allergy Asthma Clin Immunol 13:51
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Reber, Laurent L; Gillis, Caitlin M; Starkl, Philipp et al. (2017) Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide. J Exp Med 214:1249-1258
Sampath, Vanitha; Tupa, Dana; Graham, Michelle Toft et al. (2017) Deciphering the black box of food allergy mechanisms. Ann Allergy Asthma Immunol 118:21-27

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