Journal
ALLERGY
Volume 76, Issue 7, Pages 2153-2165Publisher
WILEY
DOI: 10.1111/all.14716
Keywords
allergen immunotherapy; biTregs; CpG‐ ODN; Fel d 1; TNFR2
Categories
Funding
- Ministry of Higher Education and Research of Luxembourg through the intramural research program of the Luxembourg Institute of Health
- Luxembourg National Research Fund (FNR) through the FNRPRIDE program NEXTIMMUNE for doctoral education [PRIDE/11012546/NEXTIMMUNE]
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This study aims 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 at a higher dose, and shows that this approach reverts all major hallmarks of cat allergy, with the engagement of pDC-Treg and B-cell axes and the emergence of a biTreg population. The results suggest the potential of CpG adjuvant in inducing allergen-specific tolerance in patients with cat allergy or other allergic diseases.
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(+) FoxP3(hi) 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.
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