Understanding the Variability of Peanut‐Oral Immunotherapy Responses by Multi‐Omics Profiling of Immune Cells

Background Oral immunotherapy (OIT) induces desensitization in peanut allergy, yet 15%–30% of patients do not respond, and a significant risk of anaphylaxis due to treatment remains. In a placebo‐controlled peanut OIT trial, this study identifies molecular drivers of OIT responsiveness through multi‐omics profiling in immune cells. Methods Immunoglobulins, cytokines, transcriptome, and DNA methylome profiles were analyzed in peanut‐stimulated and unstimulated peripheral blood mononuclear cells isolated from peanut‐allergic children before and after treatment. Multi‐omics profiling focused on OIT responsiveness within the active treatment arm. Additional subgroup analyses were performed to further elucidate molecular mechanisms and potential biomarkers. Results Complete responders, tolerating 4500 mg of peanut protein, exhibited lower pre‐treatment peanut‐specific IgE and Th2 cytokine production (IL‐4, IL‐5) compared to incomplete responders who tolerated ≤ 1000 mg of peanut protein after treatment. Our primary analysis identified 184 differentially expressed genes and 1001 differentially methylated genes, enriched for innate (ILC3) and adaptive (CD8αα subset of CD8 + T cells) immune cells, alongside γδ T cells and exosomes, highlighting gastrointestinal regulatory processes as central to OIT success. We found a marked downregulation of immunoglobulin genes in patients receiving peanut compared to placebo, suggesting OIT‐induced modulation of B‐cell activity. Functional networks revealed a marked imbalance contrasting regulatory T‐cell responses and B‐cell suppression in the complete responders with innate immune signaling and metabolic stress in the incomplete responders. Conclusion This multi‐omics approach underscores the importance of gastrointestinal immune mechanisms underlying the variation in peanut oral immunotherapy responses and offers potential biomarkers for improving treatment strategies.