Early IL-10 producing B-cells and coinciding Th/Tr17 shifts during three year grass-pollen AITResearch in context
Ulrich M. Zissler,
Constanze A. Jakwerth,
Ferdinand M. Guerth,
Lisa Pechtold,
Juan Antonio Aguilar-Pimentel,
Katharina Dietz,
Kathrin Suttner,
Guido Piontek,
Bernhard Haller,
Zuzana Hajdu,
Matthias Schiemann,
Carsten B. Schmidt-Weber,
Adam M. Chaker
Affiliations
Ulrich M. Zissler
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany
Constanze A. Jakwerth
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany
Ferdinand M. Guerth
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany
Lisa Pechtold
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Ismaninger Str. 22, Munich 81675, Germany
Juan Antonio Aguilar-Pimentel
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany
Katharina Dietz
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany
Kathrin Suttner
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany
Guido Piontek
Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Ismaninger Str. 22, Munich 81675, Germany
Bernhard Haller
Institute of Medical Informatics, Statistics and Epidemiology, Medical School, Technical University of Munich, Grillparzerstr. 18, Munich 81675, Germany
Zuzana Hajdu
Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Ismaninger Str. 22, Munich 81675, Germany
Matthias Schiemann
Department of Microbiology and Hygiene, Medical School, Technical University of Munich, Trogerstr. 30, Munich 81675, Germany
Carsten B. Schmidt-Weber
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany
Adam M. Chaker
Center of Allergy & Environment (ZAUM), German Research Center for Environmental Health, Member of the German Center for Lung Research (DZL), Helmholtz Center Munich, Technical University of Munich (TUM), Biedersteiner Str. 29, Munich 80802, Germany; Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Ismaninger Str. 22, Munich 81675, Germany; Corresponding author at: Department of Otorhinolaryngology and Center of Allergy and Environment (ZAUM), TUM Medical School, Klinikum rechts der Isar, Technical University Munich, Ismaninger Strasse 22, Munich 81675, Germany.
Background: Allergen-specific immunotherapy (AIT) is a causative treatment in allergic airway disease, comprising long-term allergen administration and requiring three years of treatment. Mechanisms and biomarkers that translate into clinical efficacy remain urgently needed. Methods: In an exploratory observational allergy cohort we phenotyped 32 grass-pollen allergic patients with hayfever undergoing AIT for over three years and controls using local and systemic samples for ex vivo FACS, nasal transcriptomes and in vitro phleum-stimulation at critical time windows six hours after therapeutic allergen administration and during peak-season responses. Findings: The up-dosing phase is marked by increased IL-10+ B-cells with allergen-specific PD-L1 up-regulation, while effector Th1/Th17 cells and CCR6+IL-17+FoxP3+T-cells decrease. The conversion phase exhibits Th17 recovery in the absence of Th2 cells. The tolerance-mounting phase after three years of treatment is characterized by induction of Tregs while Th2 and phleum-specific Th17 responses decrease. Notably, high ratios of circulating Breg/Th17 following initial AIT correlate significantly with clinical improvement after three years. Interpretation: Our exploratory data hypothezise differential shifts in the hierarchy of tolerance in three distinct phases of AIT characterized by conversion of regulatory against pro-inflammatory mechanisms, of which the Breg/Th17 ratio after initial treatment emerges as potential early prediction of AIT efficacy. Fund: This study was partially funded by Allergopharma GmbH & Co. KG, intramural funding and the German Center for Lung Research (DZL). Keywords: Allergic Rhinitis, Allergy, Specific Immunotherapy, Biomarker, Prediction, Surrogate, Tolerance, Regulatory B-cells (Bregs), Regulatory T-cells (Tregs)
