Threshold, Severity, and Immunotherapy of Peanut Allergy

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SUMMARY Peanut allergy has tripled in prevalence in recent decades, affecting up to 5% of children in some US regions. Peanut allergy is typically life-long, can be fatal, and impacts quality of life. These factors support our rationale to continue studying peanut allergy for this renewal of our AADCRC. Our application addresses several unmet needs in peanut allergy research and care. The unpredictable severity of peanut allergic reactions is a burden for affected individuals. Current assays have limited utility in predicting reaction severity. Expanding our mechanistic understanding of reaction severity is an essential step for guiding better treatment for peanut allergy. Although oral immunotherapy (OIT) is gaining clinical use for desensitization, only one product designed for low-threshold children is approved, and response to treatment is highly variable. Preliminary results from a randomized clinical trial within our current AADCRC (2018-2023) support that there is a common phenotype of high-threshold peanut allergy that is easy to treat. All who have completed high-dose peanut butter OIT in our trial have demonstrated sustained unresponsiveness following OIT without any adverse effects. Similar to the revolutionizing impact that prior Mount Sinai AADCRC studies of baked egg and baked milk had on the treatment and understanding of egg and milk allergy, our current AADCRC’s findings could alter the approach to peanut allergy worldwide for the ~50% who have high threshold peanut allergy. These findings also emphasize that further research is needed to understand mechanisms underlying OIT and OIT response across the threshold spectrum. The contrasting outcomes motivate examination of individuals of all thresholds undergoing OIT to identify endotypes that can be used to personalize treatment. The next stage of the Mount Sinai AADCRC will be a dual core, dual project program that focuses on new questions about reaction severity, threshold, and immunotherapy of peanut allergy. We will address our overall hypothesis that dynamic changes in circulating cellular subpopulations, molecular networks, and metabolic pathways are mechanistically linked to peanut reaction severity and response to OIT. We will synergize Mount Sinai’s cutting edge clinical OIT program via a clinical core (PATHWAYS) and administrative core with two complementary research projects (ROSETTA and IMPALA) that will extend understandings of reaction severity, threshold, and immunotherapy of peanut allergy. We will build on our innovation of assaying time series of blood samples from children undergoing double-blind, placebo-controlled food challenges to study subjects of all thresholds before and after OIT to identify in vivo mechanisms of reaction severity. ROSETTA will leverage integrative transcriptomics and systems biology to uncover mechanisms underlying reaction severity, OIT, and endotypes of OIT response. IMPALA will complement this effort with cell- and pathway-specific studies to expand our understanding of innate immunity in anaphylaxis. Our integrated program will enrich mechanistic understandings, advance personalized medicine, and identify new therapeutic targets for peanut allergy.