Oral immunotherapy suppresses peripheral blood transcriptomic response to peanut in peanut allergy
Lingdi Zhang, Yoojin Chun, Kyle Reed, Galina Grishina, Tracy Lo, Julie Wang, Scott Sicherer, Supinda Bunyavanich
J Allergy Clin Immunol; 2026 Feb; 157(2):398-408. doi: 10.1016/j.jaci.2025.10.030.
Abstract
Background: Peanut allergy is a common condition without a cure. Oral immunotherapy (OIT) induces desensitization, but its mechanisms are not fully understood.
Objective: We sought to characterize how OIT alters the peripheral blood transcriptome in peanut allergy.
Methods: We studied peripheral blood transcriptomes as 73 children aged 4 to 14 years with high-threshold peanut allergy received OIT or avoided peanut in a randomized trial. Participants randomized to OIT (n = 38) ingested peanut daily, with the dose increased every 8 weeks until they reached 3396 mg or 72 weeks had passed. Participants randomized to avoidance (n = 35) avoided peanut for equivalent periods. Double-blind, placebo-controlled food challenges were conducted at baseline, after treatment, and after OIT cessation. Peripheral blood samples were collected at all double-blind, placebo-controlled food challenges. Sequencing of peripheral blood RNA, statistical analyses, and machine learning were performed.
Results: The entire OIT group (100%) achieved desensitization compared with 21% in the avoidance group. With peanut exposure, OIT-treated participants demonstrated marked suppression of a 295-transcript signature representing neutrophil degranulation and IL-4 and IL-13 signaling. Machine learning identified 27 transcripts that classified OIT-induced desensitization in independent participants with 80% accuracy. Highly ranked transcript classifiers included FOS, NDST1, LTB4R, and IER. These transcripts remained suppressed after OIT cessation. Lower levels of these transcripts were also observed in non-peanut-allergic individuals.
Conclusions: OIT markedly suppressed transcriptional processes triggered by peanut exposure, paralleling clinical desensitization, and persisting after OIT cessation. Machine learning prioritized 27 transcripts that classified OIT-induced desensitization with high accuracy. These findings advance mechanistic understanding of OIT and point to potential therapeutic targets for peanut allergy.
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