Multi-omics in Severe Asthma From Olive Pollen Allergy

Overview

Patients with severe olive pollen allergy exhibit characteristic sensitization profiles, marked by strong recognition of minor allergens like Ole e 7, and, more importantly, show poor clinical responses to pharmacological treatments and immunotherapy. Previous studies have revealed that these patients experience a permanent immunological dysfunction (notably, dysregulated effector T-cell function) leading to a systemic inflammatory state that persists beyond the pollen season. The hypothesis is that short-term treatment (6 months) with Dupilumab can stabilize and reverse the inflammatory state in patients with severe olive pollen allergy (Project PI22/01737), enabling them to transition to conventional allergen immunotherapy. This study aims to deepen our understanding of the mechanisms underlying this immunological stabilization through multi-omics profiling (metabolomics, proteomics, transcriptomics) to explain the resolution of inflammation. Specifically, the goal is to restore an effective regulatory T-cell response, allowing for allergen-specific immunotherapy, which can be administered for three years in routine clinical practice as the only treatment capable of altering the disease's progression. Since immunotherapy relies on functional regulatory T-cell responses, this approach could validate a therapeutic strategy for these patients that modifies the disease long-term, breaking the cycle of chronic inflammation. This would reduce dependency on costly biologic treatments and significantly improve the quality of life.

Olive pollen (Olea europaea) is one of the leading causes of respiratory allergy in Mediterranean countries. Among the 14 olive pollen allergens identified to date, Ole e 1 is the major sensitizing allergen, whereas sensitization to Ole e 7 is strongly associated with a severe clinical phenotype in regions with intense olive cultivation, such as Córdoba (Spain). This phenotype is characterized by persistent airway inflammation, poor asthma control, and reduced response to allergen immunotherapy despite standard treatment. Previous studies have demonstrated that severe olive pollen allergy is associated with a predominant type 2 inflammatory response, including increased frequencies of Th2 cells and type 2 innate lymphoid cells (ILC2), together with an imbalance between Th2 and Th1 immune responses. These immunological alterations are considered major contributors to persistent airway inflammation and reduced clinical efficacy of allergen immunotherapy. Dupilumab, a fully human monoclonal antibody targeting the interleukin-4 receptor alpha (IL-4Rα), inhibits signaling mediated by both IL-4 and IL-13 and has demonstrated efficacy in several type 2 inflammatory diseases, including severe asthma, chronic rhinosinusitis with nasal polyps, and atopic dermatitis. Short-term treatment with biological agents has also been shown to restore immune homeostasis and improve subsequent responses to allergen immunotherapy in selected allergic populations. This observational study is conducted within the framework of the ISCIII-funded competitive research project PI22/01737. The objective is to characterize longitudinal immunological and molecular changes associated with allergen immunotherapy in severe olive pollen-induced allergic asthma and to evaluate the influence of previous short-term dupilumab treatment on these responses under routine clinical practice conditions. Clinical follow-up will be complemented by comprehensive multi-omics analyses, including targeted serum metabolomics, serum proteomics, transcriptomic profiling, and peripheral T-cell immunophenotyping. These complementary approaches are intended to identify biological pathways associated with immune regulation, inflammatory activity, and the development of long-term immune tolerance during allergen immunotherapy. Comparisons will be performed between individuals previously treated with a short course of dupilumab before initiation of allergen immunotherapy and individuals receiving conventional treatment without previous biological therapy. The integration of clinical, immunological, and multi-omics data is expected to improve the understanding of mechanisms associated with successful allergen immunotherapy and to identify candidate biomarkers related to treatment response and immune stabilization. Because of the exploratory nature of the study and the complexity of the molecular analyses, the findings will primarily generate biological hypotheses and candidate biomarkers for validation in larger prospective cohorts. Identification of reproducible molecular signatures associated with successful immune modulation may contribute to the development of more personalized therapeutic strategies for severe olive pollen allergy and optimize the use of allergen immunotherapy in this population.