International Rhinologic Society Rhinology 0300-0729 2025 11 30 Nasal secretions trace epithelial type 2 response to allergen-specific immunotherapy EN C.A. Jakwerth Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative U.M. Zissler Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative M. Oelsner Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative L. PechtoldCenter of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany L. zur BonsenCenter of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany M. PlaschkeCenter of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany J. KauCenter of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany M. DavidovicCenter of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany M. MootzCenter of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany B. Haller Institute of Medical Informatics, Statistics and Epidemiology, Medical School, Technical University of Munich, Munich, Germany A.M. ChakerCenter of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany C.B. Schmidt- Weber Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany and Member of the Helmholtz I and I Initiative Journal Article 3245 10.4193/Rhin24.038 BACKGROUND: Allergen-specific immunotherapy (AIT) is a disease-modifying therapy and is effective to reduce the symptoms of grass pollen-allergy. The airway epithelium of these patients releases inflammatory mediators including type-2 cytokines, which are associated with cellular processes involved in the symptomatic response of the affected tissue. Aim of the study was to identify epithelial biomarkers indicating AIT progress. METHODS: In an exploratory, observational allergy cohort, we longitudinally phenotyped 56 grass pollen-allergic patients undergoing AIT for over three years and 18 controls using nasal secretions at critical time windows during therapy to assess peak-season responses along the course of therapy. Type-2 cytokine protein levels were analyzed using the high-sensitivity multiplex electrochemiluminescence mesoscale technique. RESULTS: The type-2 cytokines CCL26 and POSTN oscillated seasonally, in contrast to TSLP and IL-33. However, only POSTN was reduced over the three-year AIT progression. In addition to POSTN, IL-24 and IL-37 levels were continuously reduced during AIT, while IFN-g and CCL27 were increased. Compared to healthy individuals, AIT did not restore healthy secretion levels but rather induced a novel homeostasis CONCLUSION: Nasal secretions trace the epithelial response during different phases of AIT. We demonstrate that AIT only partially controls the epithelial type 2 cytokine CCL26, which also adapts to seasonal changes, while POSTN and IL-24 are potential indicators of therapy success. Therefore, nasal secretions represent a promising, non-invasive tool for monitoring seasonal progress of AIT.