Serum 25-dihydroxyvitamin D levels correlate with CD4+Foxp3+ T-cell numbers in moderate/severe asthma

Chambers, Emma S.; Nanzer, AM; Richards, David F.; Ryanna, Kimuli; Freeman, Anna; Timms, Philip; Martineau, Adrian R.; Griffiths, Christopher J.; Corrigan, Christopher; Hawrylowicz, Catherine M.

doi:10.1016/j.jaci.2012.04.022

Cited by 46 publications

(52 citation statements)

References 10 publications

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“…Using this unique patient cohort, we recorded a positive correlation between serum 25-hydroxyvitamin D3 levels with the frequency of CD25 + Foxp3 + T cells in the airways, complimenting our in vitro observations. Additionally, we have very recently observed that the frequency of CD4 + CD127 low Foxp3 + T cells in the periphery of steroid sensitive is higher than in steroid refractory adult moderate to severe asthmatics, and go on to demonstrate a significant correlation between serum vitamin D status and the number of these cells in the periphery [37]. Together, these association data support the concept that vitamin D status may control Foxp3 + Treg frequencies in vivo, which could represent a mechanism whereby vitamin D treatment dampens asthma symptoms.…”

Section: Discussionmentioning

confidence: 93%

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

et al. 2012

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1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4 + T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3 + regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3 + and IL-10 + CD4 + T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3 + and IL-10 + T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3 + Treg cells over their Foxp3 − T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3 + expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4 + Foxp3 + T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10 + and Foxp3 + Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.Keywords: 1α,25-Dihydroxyvitamin D3 r Asthma r Immune regulation r Regulatory T cells Supporting Information available online IntroductionConsiderable interest exists in the therapeutic potential of regulatory T (Treg) cells to treat a range of immune-mediated patholoCorrespondence: Dr. Catherine M. Hawrylowicz e-mail: catherine.hawrylowicz@kcl.ac.uk gies in humans. This is partly based on evidence obtained from animal models of human disease demonstrating the capacity of Treg cells to control transplant rejection, and to successfully treat autoimmune and allergic disease [1]. Two broad therapeutic * These authors contributed equally to this work. [11]. These studies demonstrate a correlation between therapeutic efficacy and increased frequency or quantities of CD4 + CD25 + T cells, IL-10, TGF-β, and CTLA-4.Our earlier studies have highlighted the capacity of 1α25VitD3 to promote human CD4 + IL-10 secreting Treg cells (IL-10-Treg) in culture both alone [12] and in concert with glucocorticoids such as dexamethasone [13,14]. Furthermore, treatment of severe steroid refractory asthma patients with 1α25VitD3 in vivo directly increased IL-10 gene expression in CD3 + CD4 + T cells [12], and restored the impaired steroid-induced IL-10 response in CD4 + cells in vitro [14,15].The present study was designed to further investigate the mechanisms underlying the therapeutic potential of 1α25VitD3 in the context of asthmatic disease, and to determine effects on the induction of both IL-10 + and Foxp3 + T cells. Specifically, we have examined the effects of 1α25VitD3 on total, unfractionated CD4 + T-cell populations, r...

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Section: Discussionmentioning

confidence: 93%

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

et al. 2012

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“…Gating strategy was as described, to identify cells that we have previously shown to be regulatory in cultures [19]. For both HDM and GRASS, Depig-pol extracts expanded similar numbers of CD4 + CD25 + Foxp3 hi CD127 lo (regulatory T cells) compared to native extracts, but reduced numbers of CD4 + CD25 + Foxp3 lo CD127 + (effector cells, Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…However, our recent data shows that 1α, 25-dihydroxyvitamin D3 can also expand Foxp3 hi Tregs [20]. The type of Treg emerging depended on the concentration of 1α, 25-dihydroxyvitamin D3 in cultures, and the cytokine milieu and essentially no co-expression of Foxp3 and IL-10 was observed, although both populations exhibited comparable suppressive activity [19,20]. The present findings are in keeping with that data in that a relatively higher concentration favoured Foxp3 hi Tregs (albeit 10 -7 M here rather than 10 -6 M in an anti-CD3 driven culture system), and in these conditions IL-10 producing T cells were not detected (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, there is much current interest in 1α, 25-dihydroxyvitamin D3, which can expand both induced IL-10-producing and Foxp3+ Treg in vitro, and improved effects of immunotherapy in animal models [18-21]. Vitamin D status and/or treatment of human volunteers with vitamin D derivatives correlated with or increased Foxp3+ T cell frequency in the periphery [19] and the airway in asthmatics [20] and IL-10 producing Treg in the periphery [18]. …”

Section: Introductionmentioning

confidence: 99%

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Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3

et al. 2014

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BackgroundAllergen immunotherapy (SIT) is the only treatment for allergic disease capable of modifying disease long term. To reduce the risk of anaphylaxis from SIT, allergen-extracts have been modified by polymerisation with glutaraldehyde to reduce IgE binding. It is suggested that these allergoid extracts also have reduced T cell activity, which could compromise clinical efficacy. Effective SIT is thought to act through regulatory T cells (Tregs) rather than activation of effector T cells. There is no published data on the activity of modified extracts on Tregs.ResultsWe compared the capacity of modified (depigmented-polymerised) versus unmodified (native) allergen extracts of grass pollen and house dust mite to stimulate proliferation/cytokine production and to modulate Treg/effector T cell frequency in cultures of peripheral blood mononuclear cells (PBMC), from volunteers sensitised to both allergens in vitro. Depigmented-polymerised allergen extracts stimulated less proliferation of PBMC, and reduced effector cell numbers after 7 days in culture than did native extracts. However, the frequency of Foxp3+ Tregs in cultures were similar to those seen with native extract so that ratios of regulatory to effector T cells were significantly increased in cultures stimulated with depigmented-polymerised extracts. Addition of 1α, 25-dihydroxyvitamin D3 further favoured Treg, and reduced effector cytokine production, but not interleukin-10.ConclusionsDepigmented-polymerised allergen extracts appear to favour Treg expansion over activation of effector T cells and this may relate to their demonstrated efficacy and safety in SIT. 1α, 25-dihydroxyvitamin D3 further reduces effector T cell activation by allergen extracts and may be a useful adjuvant for SIT.

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“…Little is known about 25(OH)D in adult asthma patients or its association with asthma severity [54,55]. More than that, 25(OH)D triggers a Hcy metabolizing enzyme and data from the Longitudinal Aging Study Amsterdam suggested a correlation between 25(OH)D status and Hcy levels [56]. The decrease in Hcy concentrations and increase in 25(OH)D also supports the possible vascular endothelial protection mechanism.…”

Section: Omalizumab Effects On Oxidative Stress Markers Vitamin-d Anmentioning

confidence: 99%

ANTI-Ige: An Overview

Yalçın¹

2014

Glob J Allergy

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Asthma is common chronic inflammatory disease of the airways characterised by variable and attacks of cough and breathlesness, usually precipitated by an enviromental trigger (air pollution, smoke, etc). The prevalence and severity for allergic asthma have increased markedly in the last several decades. Dysregulated expression patterns of pro-and anti inflammatory mechanisms are thought to be responsible for the development of chronic inflammation. The risk of developing asthma has a strong genetic component, with estimated heritability ranging from 35 to 85%. The mechanism of action of Omalizumab in the treatment of asthma is believed to be multifactorial.

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Serum 25-dihydroxyvitamin D levels correlate with CD4+Foxp3+ T-cell numbers in moderate/severe asthma

Cited by 46 publications

References 10 publications

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3

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Serum 25-dihydroxyvitamin D levels correlate with CD4+Foxp3+ T-cell numbers in moderate/severe asthma

Cited by 46 publications

References 10 publications

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+and IL‐10+CD4+T cells

Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3

ANTI-Ige: An Overview

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The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells

The role of 1α,25‐dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3⁺and IL‐10⁺CD4⁺T cells