Gender Differences in 1,25 Dihydroxyvitamin D3 Immunomodulatory Effects in Multiple Sclerosis Patients and Healthy Subjects

Correale, Jorge; Ysrraelit, María Célica; Gaitán, María I.

doi:10.4049/jimmunol.1000588

Cited by 147 publications

(121 citation statements)

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“…This approach is especially suited to ongoing chronic diseases such as asthma that occur at high prevalence, where a simple treatment such as vitamin D supplementation would be relatively safe, acceptable to patients, and cost effective. The present study aimed to investigate the capacity of 1α25VitD3 to promote Treg cells and whether dose-dependent limitations exist.Early indications from clinical studies suggest vitamin D treatment of patients enhances T-cell expression of IL-10 in vivo, although data on the impact on Foxp3 + Treg cell frequencies in human peripheral blood are less clear [12,[23][24][25][26]. Here, we demonstrate that the active form of vitamin D3 increases the frequency of both IL-10 + and Foxp3 + cells in cultures of human peripheral blood derived CD4 + T cells.…”

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confidence: 60%

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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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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“…It is also well known that estrogen stimulates calcitriol accumulation in women (27)(28)(29)(30). Investigation of experimental autoimmune encephalomyelitis (EAE) and MS has indicated that vitamin D also has more immune-modulatory effects in women than in men (31,32). These studies indicated that a possible crosstalk exists between 17-b estradiol (E2) and calcitriol during the pathogenesis of EAE and MS. Possible mechanisms have been proposed to explain this phenomenon (32).…”

Section: Discussionmentioning

confidence: 99%

“…Investigation of experimental autoimmune encephalomyelitis (EAE) and MS has indicated that vitamin D also has more immune-modulatory effects in women than in men (31,32). These studies indicated that a possible crosstalk exists between 17-b estradiol (E2) and calcitriol during the pathogenesis of EAE and MS. Possible mechanisms have been proposed to explain this phenomenon (32). E2 can suppress CYP24A1 transcripts that encode the calcitriolinactivating enzyme (24-hydroxylase) and also enhance VDR biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Low Levels of Serum Vitamin D3 Are Associated with Autoimmune Thyroid Disease in Pre-Menopausal Women

Choi

Kim

et al. 2014

Thyroid

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Background: Low serum vitamin D levels have been associated with several autoimmune diseases, but their association with thyroid autoimmunity is unclear. We evaluated the association of serum vitamin D levels with the prevalence of autoimmune thyroid disease (AITD). Methods: Our cross-sectional study included subjects who underwent routine health checkups, which included assays of serum 25-hydroxy vitamin D3 [25(OH)D3] and anti-thyroid peroxidase antibody (TPO-Ab), as well as thyroid ultrasonography (US) between 2008 and 2012 at the Asan Medical Center. We defined AITD according to the levels of TPO-Ab and US findings. Results: A total of 6685 subjects (58% male; 42% female) were enrolled for this study. Overall prevalence of TPO-Ab positivity and both TPO-Ab/US positivity were 10.1% (6.3% male; 15.3% female) and 5.4% (2.3% male; 9.7% female) respectively. In female subjects, mean serum 25(OH)D3 levels were significantly lower in the TPO-Ab(+) (22.0 vs. 23.5 ng/mL, p = 0.030) and TPO-Ab(+)/US(+) groups (21.6 vs. 23.4 ng/mL, p = 0.027) compared with the control group, respectively. According to the levels of serum 25(OH)D3, the prevalence of TPO-Ab positivity (21.2%, 15.5%, and 12.6% in deficient, insufficient, and sufficient group, respectively; p = 0.001) and both TPO-Ab and US positivity (14.7%, 9.9%, and 7.1% in deficient, insufficient, and sufficient group, respectively; p < 0.001) decreased in female subjects. Interestingly, this pattern was significant only in pre-menopausal women ( p = 0.003 and p < 0.001; respectively), but not in postmenopausal women. Multivariate analysis indicated that the adjusted odds ratios (

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“…Furthermore, several studies in MS patients have shown that vitamin D plays an anti-inflammatory and immunomodulatory role via diverse immunological mechanisms [Mahon et al 2003;Correale et al 2009Correale et al , 2010Royal et al 2009;Bartosik-Psujek et al 2010;Smolders et al 2008aSmolders et al , 2009Smolders et al , 2010Smolders et al , 2011bLysandropoulos et al 2011], potentially resulting in beneficial effects after the start of the disease. It has also recently been reported in two different association studies that the spontaneous 25-OH-D serum level (DSL) of patients with relapsing-remitting MS (RRMS) was inversely correlated in a linear fashion with the relapse rate, which supports a protective role of vitamin D, at least at the beginning of the disease [Mowry et al 2010;Simpson et al 2010].…”

Section: Introductionmentioning

confidence: 99%

Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation

Pierrot‐Deseilligny

Rivaud-Péchoux

Clerson

et al. 2012

Ther Adv Neurol Disord

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Abstract:Background: Vitamin D could play a protective role in multiple sclerosis. Methods:In an observational, uncontrolled study, vitamin D3 supplementation (3010 IU/day on average) was given to 156 consecutive patients with relapsing-remitting multiple sclerosis, under first-line immunomodulatory therapy and with initial 25-OH-D serum level lower than 100 nmol/l (40 ng/ml). Relapses were determined for 29.1 ± 8.4 months during vitamin D and 29.8 ± 10.1 months before supplementation. The 25-OH-D level was measured before supplementation and several times during supplementation. The incidence rate of relapses before and during supplementation was estimated using negative binomial regression models with follow-up durations as offset terms. The incidence rate and incidence rate ratio of relapses at various 25-OH-D levels were also calculated using negative binomial regression models. Results: In 76 patients, immunomodulatory therapy preceded vitamin D supplementation (by 4.2 ± 2.7 years) and in 80 patients both treatments were started simultaneously. Under supplementation, the 25-OH-D level increased from 49 ± 22 nmol/l to 110 ± 26 nmol/l on average. Pooling data collected before and during supplementation, we found a significant strong inverse relationship between the relapse incidence rate and the 25-OH-D level (p < 0.0001), suggesting that vitamin D did indeed influence the relapse rate. Results of univariate, bivariate and multivariate analyses were analogous: in the multivariate model adjusted for age, disease duration and previous use of immunomodulatory therapy, every 10 nmol increase in 25-OH-D level was associated with a reduction in the relapse incidence rate of 13.7%. Dividing iteratively the population made up of pooled periods into two subgroups according to the 25-OH-D levels, the relapse incidence rate ratio decreased as the 25-OH-D level increased up to 110 nmol/l, but a plateau effect was observed beyond this limit. Conclusion: Further studies are warranted for accurate quantification of the vitamin D effect.

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Gender Differences in 1,25 Dihydroxyvitamin D3 Immunomodulatory Effects in Multiple Sclerosis Patients and Healthy Subjects

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Cited by 147 publications

References 83 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

Low Levels of Serum Vitamin D3 Are Associated with Autoimmune Thyroid Disease in Pre-Menopausal Women

Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation

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Gender Differences in 1,25 Dihydroxyvitamin D3 Immunomodulatory Effects in Multiple Sclerosis Patients and Healthy Subjects

Abstract: Material

Cited by 147 publications

References 83 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

Low Levels of Serum Vitamin D3 Are Associated with Autoimmune Thyroid Disease in Pre-Menopausal Women

Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation

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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