Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy: an observational study

Dimitrii Pogorelov; Sebastian Felix Nepomuk Bode; Xin He; Javier Ramiro-Garcia; Fanny Hedin; Wim Ammerlaan; Maria Konstantinou; Christophe M Capelle; Ni Zeng; Aurélie Poli; Olivia Domingues; Guillem Montamat; Oliver Hunewald; Séverine Ciré; Alexandre Baron; Joseph Longworth; Agnieszka Demczuk; Murilo Luiz Bazon; Ingrid Casper; Ludger Klimek; Lorie Neuberger-Castillo; Dominique Revets; Lea Guyonnet; Sylvie Delhalle; Jacques Zimmer; Vladimir Benes; Françoise Codreanu-Morel; Christiane Lehners-Weber; Ilse Weets; Pinar Alper; Dirk Brenner; Jan Gutermuth; Coralie Guerin; Martine Morisset; François Hentges; Reinhard Schneider; Mohamed H Shamji; Fay Betsou; Paul Wilmes; Enrico Glaab; Antonio Cosma; Jorge Goncalves; Feng Q Hefeng; Markus Ollert

doi:10.1038/s41467-024-54684-2

Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy: an observational study

Dimitrii Pogorelov, Sebastian Felix Nepomuk Bode, Xin He, Javier Ramiro-Garcia, Fanny Hedin, Wim Ammerlaan, Maria Konstantinou, Christophe M Capelle, Ni Zeng, Aurélie Poli, Olivia Domingues, Guillem Montamat, Oliver Hunewald, Séverine Ciré, Alexandre Baron, Joseph Longworth, Agnieszka Demczuk, Murilo Luiz Bazon, Ingrid Casper, Ludger KlimekLorie Neuberger-Castillo, Dominique Revets, Lea Guyonnet, Sylvie Delhalle, Jacques Zimmer, Vladimir Benes, Françoise Codreanu-Morel, Christiane Lehners-Weber, Ilse Weets, Pinar Alper, Dirk Brenner, Jan Gutermuth, Coralie Guerin, Martine Morisset, François Hentges, Reinhard Schneider, Mohamed H Shamji, Fay Betsou, Paul Wilmes, Enrico Glaab, Antonio Cosma, Jorge Goncalves, Feng Q Hefeng^*, Markus Ollert^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

Abstract

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.

Original language	English
Article number	10266
Number of pages	22
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-54684-2
Publication status	Published - 26 Nov 2024

Keywords

Humans
Desensitization, Immunologic/methods
Male
Female
Allergens/immunology
Adult
Middle Aged
Arthropod Venoms/immunology
Interleukin-6/metabolism
Th2 Cells/immunology
Hypersensitivity/immunology
Immune Tolerance
Interleukin-10/metabolism
Animals
Pollen/immunology
Th17 Cells/immunology
Rhinitis, Allergic, Seasonal/immunology
Monocytes/immunology
Multiomics

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Pogorelov, D., Bode, S. F. N., He, X., Ramiro-Garcia, J., Hedin, F., Ammerlaan, W., Konstantinou, M., Capelle, C. M., Zeng, N., Poli, A., Domingues, O., Montamat, G., Hunewald, O., Ciré, S., Baron, A., Longworth, J., Demczuk, A., Bazon, M. L., Casper, I., ... Ollert, M. (2024). Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy: an observational study. Nature Communications, 15(1), Article 10266. https://doi.org/10.1038/s41467-024-54684-2

@article{d85604d4e1754568bbbf3cb77aa5c7b1,

title = "Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy: an observational study",

abstract = "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. ",

keywords = "Humans, Desensitization, Immunologic/methods, Male, Female, Allergens/immunology, Adult, Middle Aged, Arthropod Venoms/immunology, Interleukin-6/metabolism, Th2 Cells/immunology, Hypersensitivity/immunology, Immune Tolerance, Interleukin-10/metabolism, Animals, Pollen/immunology, Th17 Cells/immunology, Rhinitis, Allergic, Seasonal/immunology, Monocytes/immunology, Multiomics",

author = "Dimitrii Pogorelov and Bode, {Sebastian Felix Nepomuk} and Xin He and Javier Ramiro-Garcia and Fanny Hedin and Wim Ammerlaan and Maria Konstantinou and Capelle, {Christophe M} and Ni Zeng and Aur{\'e}lie Poli and Olivia Domingues and Guillem Montamat and Oliver Hunewald and S{\'e}verine Cir{\'e} and Alexandre Baron and Joseph Longworth and Agnieszka Demczuk and Bazon, {Murilo Luiz} and Ingrid Casper and Ludger Klimek and Lorie Neuberger-Castillo and Dominique Revets and Lea Guyonnet and Sylvie Delhalle and Jacques Zimmer and Vladimir Benes and Fran{\c c}oise Codreanu-Morel and Christiane Lehners-Weber and Ilse Weets and Pinar Alper and Dirk Brenner and Jan Gutermuth and Coralie Guerin and Martine Morisset and Fran{\c c}ois Hentges and Reinhard Schneider and Shamji, {Mohamed H} and Fay Betsou and Paul Wilmes and Enrico Glaab and Antonio Cosma and Jorge Goncalves and Hefeng, {Feng Q} and Markus Ollert",

note = "Funding: 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 Article https://doi.org/10.1038/s41467-024-54684-2 Nature Communications | (2024)15:10266 20 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{\textquoteright}s 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. {\textcopyright} 2024. The Author(s).",

year = "2024",

month = nov,

day = "26",

doi = "10.1038/s41467-024-54684-2",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Pogorelov, D, Bode, SFN, He, X, Ramiro-Garcia, J, Hedin, F , Ammerlaan, W , Konstantinou, M, Capelle, CM, Zeng, N, Poli, A , Domingues, O, Montamat, G, Hunewald, O, Ciré, S, Baron, A, Longworth, J , Demczuk, A , Bazon, ML, Casper, I, Klimek, L, Neuberger-Castillo, L, Revets, D, Guyonnet, L, Delhalle, S, Zimmer, J, Benes, V, Codreanu-Morel, F, Lehners-Weber, C, Weets, I, Alper, P, Brenner, D, Gutermuth, J, Guerin, C, Morisset, M, Hentges, F, Schneider, R, Shamji, MH, Betsou, F, Wilmes, P, Glaab, E, Cosma, A, Goncalves, J, Hefeng, FQ & Ollert, M 2024, 'Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy: an observational study', Nature Communications, vol. 15, no. 1, 10266. https://doi.org/10.1038/s41467-024-54684-2

TY - JOUR

T1 - Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy

T2 - an observational study

AU - Pogorelov, Dimitrii

AU - Bode, Sebastian Felix Nepomuk

AU - He, Xin

AU - Ramiro-Garcia, Javier

AU - Hedin, Fanny

AU - Ammerlaan, Wim

AU - Konstantinou, Maria

AU - Capelle, Christophe M

AU - Zeng, Ni

AU - Poli, Aurélie

AU - Domingues, Olivia

AU - Montamat, Guillem

AU - Hunewald, Oliver

AU - Ciré, Séverine

AU - Baron, Alexandre

AU - Longworth, Joseph

AU - Demczuk, Agnieszka

AU - Bazon, Murilo Luiz

AU - Casper, Ingrid

AU - Klimek, Ludger

AU - Neuberger-Castillo, Lorie

AU - Revets, Dominique

AU - Guyonnet, Lea

AU - Delhalle, Sylvie

AU - Zimmer, Jacques

AU - Benes, Vladimir

AU - Codreanu-Morel, Françoise

AU - Lehners-Weber, Christiane

AU - Weets, Ilse

AU - Alper, Pinar

AU - Brenner, Dirk

AU - Gutermuth, Jan

AU - Guerin, Coralie

AU - Morisset, Martine

AU - Hentges, François

AU - Schneider, Reinhard

AU - Shamji, Mohamed H

AU - Betsou, Fay

AU - Wilmes, Paul

AU - Glaab, Enrico

AU - Cosma, Antonio

AU - Goncalves, Jorge

AU - Hefeng, Feng Q

AU - Ollert, Markus

N1 - Funding: 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 Article https://doi.org/10.1038/s41467-024-54684-2 Nature Communications | (2024)15:10266 20 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’s 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. © 2024. The Author(s).

PY - 2024/11/26

Y1 - 2024/11/26

N2 - 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.

AB - 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.

KW - Humans

KW - Desensitization, Immunologic/methods

KW - Male

KW - Female

KW - Allergens/immunology

KW - Adult

KW - Middle Aged

KW - Arthropod Venoms/immunology

KW - Interleukin-6/metabolism

KW - Th2 Cells/immunology

KW - Hypersensitivity/immunology

KW - Immune Tolerance

KW - Interleukin-10/metabolism

KW - Animals

KW - Pollen/immunology

KW - Th17 Cells/immunology

KW - Rhinitis, Allergic, Seasonal/immunology

KW - Monocytes/immunology

KW - Multiomics

UR - https://pubmed.ncbi.nlm.nih.gov/39592626/

U2 - 10.1038/s41467-024-54684-2

DO - 10.1038/s41467-024-54684-2

M3 - Article

C2 - 39592626

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 10266

ER -

Multiomics approaches disclose very-early molecular and cellular switches during insect-venom allergen-specific immunotherapy: an observational study

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Keywords

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