[en] Allergen-specific immunotherapy (AIT) induces immune tolerance, showing the highest success rate (>95%) for insect venom while a much lower chance for pollen allergy. However, the molecular switches leading to successful durable tolerance restoration remain elusive. The primary outcome of this observational study is the comprehensive immunological cellular characterization during the AIT initiation phase, whereas the secondary outcomes are the serological and Th2-cell-type-specific transcriptomic analyses. Here we apply a multilayer-omics approach to reveal dynamic peripheral immune landscapes during the AIT-initiation phase in venom allergy patients (VAP) versus pollen-allergic and healthy controls. Already at baseline, VAP exhibit altered abundances of several cell types, including classical monocytes (cMono), CD4+ hybrid type 1-type 17 cells (Th1-Th17 or Th1/17) and CD8+ counterparts (Tc1-Tc17 or Tc1/17). At 8-24 h following AIT launch in VAP, we identify a uniform AIT-elicited pulse of late-transitional/IL-10-producing B cells, IL-6 signaling within Th2 cells and non-inflammatory serum-IL-6 levels. Sequential induction of activation and survival protein markers also immediately occur. A disequilibrium between serum IL-6 and cMono in VAP baseline is restored at day seven following AIT launch. Our longitudinal analysis discovers molecular switches during initiation-phase insect-venom AIT that secure long-term outcomes. Trial number: NCT02931955.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Pogorelov, Dimitrii; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg ; Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg ; Center of Allergy & Environment, Technical University of Munich, Munich, Germany
Bode, Sebastian Felix Nepomuk ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg ; Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany ; Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre-University of Freiburg, Faculty of Medicine, Freiburg, Germany
Ramiro-Garcia, Javier ; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg
Hedin, Fanny; National Cytometry Platform, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
Ammerlaan, Wim; Integrated BioBank of Luxembourg, Luxembourg Institute of Health, Dudelange, Luxembourg
Konstantinou, Maria; National Cytometry Platform, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
Capelle, Christophe M ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg ; Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg ; Institute of Microbiology, ETH Zurich, Zurich, Switzerland
Zeng, Ni ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg ; Department of Life Sciences and Medicine, Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
POLI, Aurelie ; University of Luxembourg ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg ; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Domingues, Olivia; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
Montamat, Guillem ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
Hunewald, Oliver ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
Ciré, Séverine ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
BARON, Alexandre ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Translational Neuroscience > Team Rejko KRÜGER ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
LONGWORTH, Joseph ; University of Luxembourg ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
Demczuk, Agnieszka ; University of Luxembourg ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
Bazon, Murilo Luiz; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
Casper, Ingrid; Center for Rhinology and Allergology, Wiesbaden, Germany
Klimek, Ludger; Center for Rhinology and Allergology, Wiesbaden, Germany
Neuberger-Castillo, Lorie; Integrated BioBank of Luxembourg, Luxembourg Institute of Health, Dudelange, Luxembourg
Revets, Dominique; National Cytometry Platform, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
Guyonnet, Lea; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg ; Cytometry Platform, Institut Curie, Innovative Therapies in Haemostasis, INSERM, Université de Paris, Paris, France
Delhalle, Sylvie ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
ZIMMER, Jacques ; University of Luxembourg ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg
Benes, Vladimir ; Genomics Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany
Codreanu-Morel, Françoise; National Unit of Immunology-Allergology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
Lehners-Weber, Christiane; National Unit of Immunology-Allergology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
Weets, Ilse; Department of Clinical Biology/ Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, Belgium
ALPER, Pinar ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Bioinformatics Core > R3 and IT infrastructure
BRENNER, Dirk ; University of Luxembourg ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg ; Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, Odense, Denmark
Gutermuth, Jan; Department of Dermatology, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, Belgium
Guerin, Coralie ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg ; Cytometry Platform, Institut Curie, Innovative Therapies in Haemostasis, INSERM, Université de Paris, Paris, France
Morisset, Martine ; National Unit of Immunology-Allergology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg ; Allergy Unit, Angers University Hospital, Angers, France
Hentges, François; National Unit of Immunology-Allergology, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg
SCHNEIDER, Reinhard ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Shamji, Mohamed H; Immunomodulation and Tolerance Group, Allergy and Clinical Immunology, Department of National Heart and Lung Institute, Imperial College London, London, UK
BETSOU, Fay ; University of Luxembourg ; Integrated BioBank of Luxembourg, Luxembourg Institute of Health, Dudelange, Luxembourg ; CRBIP, Institut Pasteur, Université Paris Cité, Paris, France
WILMES, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Systems Ecology
COSMA, Antonio ; University of Luxembourg > Faculty of Law, Economics and Finance > Department of Economics and Management > Team Antonio COSMA ; National Cytometry Platform, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
GONCALVES, Jorge ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > AI Modelling and Prediction
Hefeng, Feng Q ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg. Feng.Hefeng@lih.lu
OLLERT, Markus ; University of Luxembourg ; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg. Markus.Ollert@lih.lu ; Department of Dermatology and Allergy Center, Odense Research Center for Anaphylaxis, University of Southern Denmark, Odense, Denmark. Markus.Ollert@lih.lu
H2020 - 863664 - ExpoBiome - Deciphering the impact of exposures from the gut microbiome-derived molecular complex in human health and disease HE - 101136957 - COMMUTE - COMORBIDITY MECHANISMS UTILIZED IN HEALTHCARE
FnR Project :
FNR11012546 - NEXTIMMUNE - Next Generation Immunoscience: Advanced Concepts For Deciphering Acute And Chronic Inflammation, 2015 (01/01/2017-30/06/2023) - Markus Ollert FNR10907093 - CriTICS - Critical Transitions In Complex Systems: From Theory To Applications, 2015 (01/11/2016-31/08/2023) - Jorge Gonçalves FNR14254520 - i2TRON - Integrating Immune Strategies For Translational Research In Oncology And Neurology, 2020 (01/02/2021-31/07/2027) - Rejko Krueger FNR18115323 - CRIS-CD8TERA - Crispr Screening In Primary Human Cd8 T Cells Identifies Regulators Modulating Cd8 Temra Differentiation, 2023 (01/05/2024-31/12/2026) - Feng He FNR10404093 - microCancer - Non-invasive Microbiome-derived Multi-omic Biomarkers For Early-stage Colorectal Cancer Detection, 2015 (01/01/2016-30/04/2019) - Paul Wilmes FNR12691266 - cROSsfire 2.0 - Elucidating The Function Of Antioxidants And Ros On Metabolism And Inflammation In Macrophages And B Cells, 2018 (01/01/2020-31/12/2022) - Dirk Brenner FNR15796788 - Th17-ImmunoMet - Characterization Of Key Metabolic Circuits In Th17 Cells And Their Influence On Th17 Cell Mediated Pathogenic And Protective Functions., 2021 (01/01/2022-31/12/2024) - Dirk Brenner FNR16954531 - CoVaLux - Covid-19, Vaccination And Longer-term Health Consequences Of Covid-19 In Luxembourg, 2021 (01/12/2021-30/11/2024) - Paul Wilmes
Funders :
European Union
Funding text :
We acknowledge all the anonymous participants in the SYS-T-ACT cohort. We appreciate all the support of research nurses especially the coordinator Jean-Yves Ferrand at CIEC of LIH and clinical nurses at Central Hospital of Luxembourg. We also thank the processing and biorepository teams at the IBBL. We acknowledge the LIH IT service unit to support and secure our resource sharing. This work was initially supported by Luxembourg Personalized Medicine Consortium (PMC, 2015 to M.O. and F.Q.H.), followed by Luxembourg National Research Fund (FNR) PRIDE programs (11012546/NEXTIMMUNE for D.P. and G.M. coordinated by M.O., 10907093/CriTiCS for C.M.C. supervised by F.Q.H. and coordinated by J. Goncalves and 14254520/i2TRON for A.D. co-coordinated by M.O.) and individual FNR AFR program (PHD-2015-1/9989160 for N.Z. coordinated by F.Q.H.) and EAACI long-term fellowship (2016, S.F.N.B.; 2022, M.L.B). F.Q.H is supported by the FNR CORE program (C23/BM/18115323) and HPC Bridges program (18886016). F.Q.H and M.O. acknowledge funding from the Horizon Europe project COMMUTE under the grant agreement No. 101136957. Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HADEA). Neither the European Union nor the granting authority can be held responsible for them. P.W. has received funding from the European Research Council (ERC) under the European Union\u2019s Horizon 2020 research and innovation program (grant agreement No. 863664) and the FNR CORE program under the grant CORE/15/BM/10404093. D.B. is supported by the FNR CORE program (C18/BM/12691266 and C21/BM/15796788). The work was further supported by the Luxembourg Government through the CoVaLux programme (16954531, M.O. and P.W.). A.P. is supported by the Action Lions Vaincre le Cancer. Some icons in our Figures were created with BioRender.com.
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