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 (CyTOF) 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.
Bibliografisk noteFunding Information:
Dr. C. Leonard reports a patent WO2019/076478Al pending, and a patent WO2019/076477Al pending. G. Montamat, C. Davril, O. Domingues, O. Hunewald, D. Revets and Dr. C. Guerin: nothing to disclose. Dr. S. Blank reports non‐financial support from ALK‐Abellò, grants, personal fees and non‐financial support from Bencard Allergie GmbH, personal fees from Teomed AG, grants from Leti Pharma, grants and personal fees from Thermo Fischer Scientific, grants from Allergy Therapeutics, outside the submitted work. J. Heckendorn, G. Jardon and Dr. F. Hentges: nothing to disclose. Dr. M. Ollert reports that he is a cofounder of Tolerogenics SARL, Luxembourg, during the conduct of the study; personal fees from Hycor Diagnostics, personal fees from Thermo Fischer/Phadia, outside the submitted work; In addition, Dr. Ollert has a patent WO2019/076478Al pending, and a patent WO2019/076477Al pending.
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