IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

Böhm, Livia; Maxeiner, Joachim; Meyer-Martin, Helen; Reuter, Sebastian; Finotto, Susetta; Klein, Matthias; Schild, Hansjörg; Schmitt, Edgar; Bopp, Tobias; Taube, Christian

doi:10.4049/jimmunol.1401612

Cited by 94 publications

(79 citation statements)

References 53 publications

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“…Additionally, systemic HDM-specific IgG 1 responses were also increased over the course of antigen exposure and were significantly elevated in long-term HDM mice relative to short- and intermediate-term HDM mice. Successful courses of allergen-specific immunotherapy (the only etiological therapy for treatment of asthma and allergy) is commonly associated with increases in IgG 1 (murine equivalent of IgG4 in humans) in both mice [30] and humans [31]. Murine IgG 1 /human IgG 4 have been thought to act as blocking antibodies that can compete with IgE for allergen binding.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation

Bracken¹,

Adami²,

Szczepanek³

et al. 2015

Int Arch Allergy Immunol

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Background: Allergic asthma is a major cause of worldwide morbidity and results from inadequate immune regulation in response to innocuous, environmental antigens. The need exists to understand the mechanisms that promote nonreactivity to human-relevant allergens such as house dust mite (HDM) in order to develop curative therapies for asthma. The aim of our study was to compare the effects of short-, intermediate- and long-term HDM administration in a murine asthma model and determine the ability of long-term HDM exposure to suppress allergic inflammation. Methods: C57BL/6 mice were intranasally instilled with HDM for short-term (2 weeks), intermediate-term (5 weeks) and long-term (11 weeks) periods to induce allergic airway disease (AAD). The severity of AAD was compared across all stages of the model via both immunological and pulmonary parameters. Results: Short- and intermediate-term HDM exposure stimulated the development of AAD that included eosinophilia in the bronchoalveolar lavage fluid (BALF), pronounced airway hyperreactivity (AHR) and evidence of lung inflammation. Long-term HDM exposure promoted the suppression of AAD, with a loss of BALF eosinophilia and AHR despite persistent mononuclear inflammation in the lungs. Suppression of AAD with long-term HDM exposure was associated with an increase in both Foxp3+ regulatory T cells and IL-10-positive alveolar macrophages at the site of inflammation. Conclusions: This model recapitulates the key features of human asthma and may facilitate investigation into the mechanisms that promote immunological tolerance against clinically relevant aeroallergens.

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Section: Discussionmentioning

confidence: 99%

Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation

Bracken¹,

Adami²,

Szczepanek³

et al. 2015

Int Arch Allergy Immunol

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“…One possible explanation for the development of this maladaptive inflammatory response is the functional insufficiency of the regulatory T cell (Treg) compartment [4–8]. Current evidences in the literature suggest that this functional insufficiency likely results from both decreased Treg cell numbers and Treg cell dysfunction [6,7,9–11]. …”

Section: Introductionmentioning

confidence: 99%

Ex vivo modulation of the Foxo1 phosphorylation state does not lead to dysfunction of T regulatory cells

et al. 2017

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Peripheral regulatory CD4+ T cells (Treg cells) prevent maladaptive inflammatory responses to innocuous foreign antigens. Treg cell dysfunction has been linked to many inflammatory diseases, including allergic airway inflammation. Glucocorticoids that are used to treat allergic airway inflammation and asthma are thought to work in part by promoting Treg cell differentiation; patients who are refractory to these drugs have defective induction of anti-inflammatory Treg cells. Previous observations suggest that Treg cells deficient in the transcription factor FoxO1 are pro-inflammatory, and that FoxO1 activity is regulated by its phosphorylation status and nuclear localization. Here, we asked whether altering the phosphorylation state of FoxO1 through modulation of a regulatory phosphatase might affect Treg cell function. In a mouse model of house dust mite-induced allergic airway inflammation, we observed robust recruitment of Treg cells to the lungs and lymph nodes of diseased mice, without an apparent increase in the Treg cytokine interleukin-10 in the airways. Intriguingly, expression of PP2A, a serine/threonine phosphatase linked to the regulation of FoxO1 phosphorylation, was decreased in the mediastinal lymph nodes of HDM-treated mice, mirroring the decreased PP2A expression seen in peripheral blood monocytes of glucocorticoid-resistant asthmatic patients. When we asked whether modulation of PP2A activity alters Treg cell function via treatment with the PP2A inhibitor okadaic acid, we observed increased phosphorylation of FoxO1 and decreased nuclear localization. However, dysregulation of FoxO1 did not impair Treg cell differentiation ex vivo or cause Treg cells to adopt a pro-inflammatory phenotype. Moreover, inhibition of PP2A activity did not affect the suppressive function of Treg cells ex vivo. Collectively, these data suggest that modulation of the phosphorylation state of FoxO1 via PP2A inhibition does not modify Treg cell function ex vivo. Our data also highlight the caveat in using ex vivo assays of Treg cell differentiation and function, in that while these assays are useful, they may not fully recapitulate Treg cell phenotypes that are observed in vivo.

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“…Yet, Tregs and IL-10, an anti-inflammatory cytokine secreted by these cells, have been implicated in the improvement of asthma [8]. In a recent study, B cells were attributed an important role in T H 2 responses and airway inflammation [9].…”

Section: Introductionmentioning

confidence: 99%

Regulatory T and B Cells in Asthmatic Women: Variations From Pregnancy to Postpartum

Martins¹,

Lima²,

Nunes³

et al. 2017

J Investig Allergol Clin Immunol

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Background and Objectives: Allergic asthma and rhinitis are common in pregnancy. The immune mechanisms underlying the effects of asthma on pregnancy and vice versa are not completely understood. The aim of this study was to investigate changes in regulatory T and B cells in asthmatic women from late pregnancy to postpartum. Methods: Four groups of women were enrolled for this study: asthmatic (n=23) and healthy (n=43) third trimester-pregnant women and asthmatic (n=33) and healthy (n=35) nonpregnant women. Pregnant women were also evaluated postpartum (>6 weeks after delivery). Blood samples were taken from each woman and flow cytometry was used to characterize circulating regulatory T cells (Tregs) and regulatory B cells (Bregs). Foxp3 expression was assessed in CD4

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IL-10 and Regulatory T Cells Cooperate in Allergen-Specific Immunotherapy To Ameliorate Allergic Asthma

Cited by 94 publications

References 53 publications

Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation

Long-Term Exposure to House Dust Mite Leads to the Suppression of Allergic Airway Disease Despite Persistent Lung Inflammation

Ex vivo modulation of the Foxo1 phosphorylation state does not lead to dysfunction of T regulatory cells

Regulatory T and B Cells in Asthmatic Women: Variations From Pregnancy to Postpartum

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