Contribution of regulatory T cells to alleviation of experimental allergic asthma after specific immunotherapy

• Published in: Clinical and experimental allergy Vol. 42; no. 10; pp. 1519 - 1528
• Main Authors: Maazi, H., Shirinbak, S., Willart, M., Hammad, H. M., Cabanski, M., Boon, L., Ganesh, V., Baru, A. M., Hansen, G., Lambrecht, B. N., Sparwasser, T., Nawijn, M. C., van Oosterhout, A. J. M.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01-10-2012; Blackwell; Wiley Subscription Services, Inc
• Subjects: allergen immunotherapy; Animals; asthma; Asthma - immunology; Asthma - therapy; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Chronic obstructive pulmonary disease, asthma; Desensitization, Immunologic - methods; Disease Models, Animal; eosinophil; Eosinophils - immunology; Female; Forkhead Transcription Factors - metabolism; FOXP3; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Hyper-reactivity; IgE; Interleukin-2 Receptor alpha Subunit - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Ovalbumin - administration & dosage; Ovalbumin - immunology; Pneumology; regulatory T cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Treatment Outcome; Immunopathology; Lung disease; Allergy; Desensitization; Hyperreactivity; allergen immunotherapy; Respiratory disease; IgE; Granulocyte; Hyper-reactivity; Experimental study; FOXP3; Eosinophil; Asthma; regulatory T cells; Immunology; Treatment; Immunotherapy; T-Lymphocyte; Bronchus disease; Obstructive pulmonary disease; Regulatory cell; Transcription factor FOXP3
• ISSN: 0954-7894; 1365-2222
• DOI: 10.1111/j.1365-2222.2012.04064.x

Summary
Background
Allergen‐specific immunotherapy (SIT) has been used since 1911, yet its mechanism of action remains to be elucidated. There is evidence indicating that CD4+FOXP3+ regulatory T cells (Treg cells) are induced during SIT in allergic patients. However, the contribution of these cells to SIT has not been evaluated in vivo.
Objective
To evaluate the in vivo contribution of (i) CD4+ CD25+ T cells during SIT and of (ii) SIT‐generated inducible FOXP3+ Treg cells during allergen exposure to SIT‐mediated suppression of asthmatic manifestations.
Methods
We used a mouse model of SIT based on the classical OVA‐driven experimental asthma. Treg cells were quantified by flow cytometry 24 and 96 h post SIT treatment. We depleted CD4+CD25+ T cells prior to SIT, and CD4+FOXP3+ T cells prior to allergen challenges to study their contribution to the suppression of allergic manifestations by SIT treatment.
Results
Our data show that depletion of CD4+CD25+ T cells at the time of SIT treatment reverses the suppression of airway hyperresponsiveness (AHR), but not of airway eosinophilia and specific IgE levels in serum. Interestingly, the number of CD4+CD25+FOXP3+ T cells is transiently increased after SIT in the spleen and blood, suggesting the generation of inducible and presumably allergen‐specific Treg cells during treatment. Depletion of CD4+FOXP3+ Treg cells after SIT treatment partially reverses the SIT‐induced suppression of airway eosinophilia, but not of AHR and serum levels of specific IgE.
Conclusion and clinical relevance
We conclude that SIT‐mediated tolerance induction towards AHR requires CD4+CD25+ T cells at the time of allergen injections. In addition, SIT generates CD4+CD25+FOXP3+ T cells that contribute to the suppression of airway eosinophilia upon allergen challenges. Therefore, enhancing Treg cell number or their activity during and after SIT could be of clinical relevance to improve the therapeutic effects of SIT.