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Comprehensive mapping of immune tolerance yields a regulatory TNF receptor 2 signature in a murine model of successful Fel d 1-specific immunotherapy using high-dose CpG adjuvant
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  • Cathy Leonard,
  • Guillem Montamat,
  • Caroline Davril,
  • Olivia Domingues,
  • Oliver Hunewald,
  • Dominique Revets,
  • Coralie Guerin,
  • Simon Blank,
  • Justine Heckendorn,
  • Gauthier Jardon,
  • François Hentges,
  • Markus Ollert
Cathy Leonard
Luxembourg Institute of Health Department of Infection and Immunity
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Guillem Montamat
Luxembourg Institute of Health Department of Infection and Immunity
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Caroline Davril
Luxembourg Institute of Health Department of Infection and Immunity
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Olivia Domingues
Luxembourg Institute of Health Department of Infection and Immunity
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Oliver Hunewald
Luxembourg Institute of Health Department of Infection and Immunity
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Dominique Revets
Luxembourg Institute of Health Department of Infection and Immunity
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Coralie Guerin
Luxembourg Institute of Health Department of Infection and Immunity
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Simon Blank
School of Medicine and Helmholtz Center Munich
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Justine Heckendorn
Luxembourg Institute of Health Department of Infection and Immunity
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Gauthier Jardon
Luxembourg Institute of Health Department of Infection and Immunity
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François Hentges
Luxembourg Institute of Health Department of Infection and Immunity
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Markus Ollert
Luxembourg Institute of Health
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Abstract

Background The prevalence of allergy to cat is expanding worldwide. Allergen-specific immunotherapy (AIT) has advantages over symptomatic pharmacotherapy and promises long lasting disease control in allergic patients. However, there is still a need to improve cat AIT regarding efficacy, safety and adherence to the treatment. Here we aim to boost immune tolerance to the major cat allergen Fel d 1 by increasing the anti-inflammatory activity of AIT with the established immunomodulatory adjuvant CpG, but at a higher dose than previously used in AIT. Methods Together with CpG, we used endotoxin-free Fel d 1 as therapeutic allergen throughout the study in a BALB/c model of allergy to Fel d 1, thus mimicking the conditions of human AIT trials. Multidimensional immune phenotyping including mass cytometry was applied to analyze AIT-specific immune signatures. Results We show that AIT with high-dose CpG in combination with endotoxin-free Fel d 1 reverts all major hallmarks of allergy. High dimensional CyTOF analysis of the immune cell signatures initiating and sustaining the AIT effect indicates the simultaneous engagement of both, the pDC-Treg and -B cell axis, with the emergence of a systemic GATA3+ FoxP3hi biTreg population. The regulatory immune signature also suggests the involvement of the anti-inflammatory TNF/TNFR2 signaling cascade in NK and B cells at an early stage and in Tregs later during AIT. Conclusion Our results highlight the potential of CpG adjuvant in a novel formulation to be further exploited for inducing allergen-specific tolerance in patients with cat allergy or other allergic diseases in the future.

Peer review status:IN REVISION

23 Jul 2020Submitted to Allergy
24 Jul 2020Assigned to Editor
24 Jul 2020Submission Checks Completed
25 Jul 2020Reviewer(s) Assigned
09 Aug 2020Review(s) Completed, Editorial Evaluation Pending
09 Aug 2020Editorial Decision: Revise Minor