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Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: Results From the D-SIRe2 Randomized Controlled Trial.
Maboshe, W, Macdonald, HM, Wassall, H, Fraser, WD, Tang, JCY, Fielding, S, Barker, RN, Vickers, MA, Ormerod, A, Thies, F
Frontiers in immunology. 2021;:623087
Abstract
BACKGROUND Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown. OBJECTIVE This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants. DESIGN 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed. RESULTS Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04). CONCLUSIONS Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation. CLINICAL TRIAL REGISTRATION https://www.isrctn.com, identifier (ISRCTN 73114576).
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Effect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial.
Barnett, JB, Dao, MC, Hamer, DH, Kandel, R, Brandeis, G, Wu, D, Dallal, GE, Jacques, PF, Schreiber, R, Kong, E, et al
The American journal of clinical nutrition. 2016;(3):942-51
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Abstract
BACKGROUND Zinc is essential for the regulation of immune response. T cell function declines with age. Zinc supplementation has the potential to improve the serum zinc concentrations and immunity of nursing home elderly with a low serum zinc concentration. OBJECTIVE We aimed to determine the effect of supplementation with 30 mg Zn/d for 3 mo on serum zinc concentrations of zinc-deficient nursing home elderly. DESIGN This was a randomized, double-blind, placebo-controlled study. Of 53 nursing home elderly (aged ≥65 y) who met eligibility criteria, 58% had a low serum zinc concentration (serum zinc <70 μg/dL); these 31 were randomly assigned to zinc (30 mg Zn/d) (n = 16) or placebo (5 mg Zn/d) (n = 15) groups. The primary outcome measure was change in serum zinc concentrations between baseline and month 3. We also explored the effects of supplementation on immune response. RESULTS Baseline characteristics were similar in the 2 groups. The difference in the mean change in serum zinc was significantly higher, by 16%, in the zinc group than in the placebo group (P = 0.007) when baseline zinc concentrations were controlled for. In addition, controlling for baseline C-reactive protein, copper, or albumin did not change the results. However, supplementation of participants with ≤60 μg serum Zn/dL failed to increase their serum zinc to ≥70 μg/dL. Zinc supplementation also significantly increased anti-CD3/CD28 and phytohemagglutinin-stimulated T cell proliferation, and the number of peripheral T cells (P < 0.05). When proliferation was expressed per number of T cells, the significant differences between groups were lost, suggesting that the zinc-induced enhancement of T cell proliferation was mainly due to an increase in the number of T cells. CONCLUSIONS Zinc supplementation at 30 mg/d for 3 mo is effective in increasing serum zinc concentrations in nursing home elderly; however, not all zinc-deficient elderly reached adequate concentrations. The increase in serum zinc concentration was associated with the enhancement of T cell function mainly because of an increase in the number of T cells.
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Reconciling Estimates of Cell Proliferation from Stable Isotope Labeling Experiments.
Ahmed, R, Westera, L, Drylewicz, J, Elemans, M, Zhang, Y, Kelly, E, Reljic, R, Tesselaar, K, de Boer, RJ, Macallan, DC, et al
PLoS computational biology. 2015;(10):e1004355
Abstract
Stable isotope labeling is the state of the art technique for in vivo quantification of lymphocyte kinetics in humans. It has been central to a number of seminal studies, particularly in the context of HIV-1 and leukemia. However, there is a significant discrepancy between lymphocyte proliferation rates estimated in different studies. Notably, deuterated (2)H2-glucose (D2-glucose) labeling studies consistently yield higher estimates of proliferation than deuterated water (D2O) labeling studies. This hampers our understanding of immune function and undermines our confidence in this important technique. Whether these differences are caused by fundamental biochemical differences between the two compounds and/or by methodological differences in the studies is unknown. D2-glucose and D2O labeling experiments have never been performed by the same group under the same experimental conditions; consequently a direct comparison of these two techniques has not been possible. We sought to address this problem. We performed both in vitro and murine in vivo labeling experiments using identical protocols with both D2-glucose and D2O. This showed that intrinsic differences between the two compounds do not cause differences in the proliferation rate estimates, but that estimates made using D2-glucose in vivo were susceptible to difficulties in normalization due to highly variable blood glucose enrichment. Analysis of three published human studies made using D2-glucose and D2O confirmed this problem, particularly in the case of short term D2-glucose labeling. Correcting for these inaccuracies in normalization decreased proliferation rate estimates made using D2-glucose and slightly increased estimates made using D2O; thus bringing the estimates from the two methods significantly closer and highlighting the importance of reliable normalization when using this technique.
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Transforming growth factor β1 (TGFβ1) in physiology and pathology.
Kajdaniuk, D, Marek, B, Borgiel-Marek, H, Kos-Kudła, B
Endokrynologia Polska. 2013;(5):384-96
Abstract
This review describes precisely the consequence of TGFβ1 prevalence in the organism, and its significant influence on physiological and pathophysiological processes. Organ and tissue distinctiveness hinder unambiguous characterisation of the cytokine. However, there are constant functions of TGFβ1 inducing no controversy: it participates in foetal development, control of cell growth and differentiation, induces fibrosis and scar formation (the process of 'wound healing'), causes the suppression of immune response, is involved in angiogenesis, the development of tumours, and inflammatory processes. Thus, TGFβ1 is a multifunctional cytokine. There are three fundamental directions of its activities: I. TGFβ1 regulates cell proliferation, growth, differentiation and cells movement. II. TGFβ1 has immunomodulatory effects. III. TGFβ1 has profibrogenic effects. TGFβ1 action can be local and systemic. This review describes TGFβ1 in pathology: colitis ulcerosa, Crohn's disease, coeliac disease, diabetic nephropathy, diabetic retinopathy and diabetic foot, pulmonary hypertension, and Alzheimer's disease. TGFβ1 and its receptors are also of interest to endocrinologists. Lack of TGFβ1-dependent growth control may result in oncogenesis: papillary, follicular and anaplastic thyroid cancers, prostate, breast and uterine cervical cancer, oesophagus, gastric, colorectal and liver cancers, NSCLC, and malignant melanoma. Excessive TGFβ1 activity is an integral part of the fibrotic processes occurring in the response to injury. An increased TGFβ1 expression has been observed in patients with pulmonary, kidney, and liver fibrosis. In chronic hepatitis, the prolonged stimulation of hepatic stellate cells being the result of chronic damage to hepatocytes results in the release of profibrogenic abundant factors such as TGFβ1 and leads to the development of liver cirrhosis. The results of experimental procedures and treatment known as anti-TGFβ1 strategy acting against the fibrosis in various tissues leads to hope regarding the use of anti-TGFβ1 strategy in clinical practice.