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.