Konijeti GG, Arora P, Boylan MR, et al. Vitamin D supplementation modulates T cell-mediated immunity in humans: results from a randomized control trial. J Clin Endocrinol Metab. 2016;101(2):533-538.
To determine whether oral supplementation with vitamin D3 affects T cell activation in those with existing vitamin D deficiency
This was a single-center ancillary study within a study looking at vitamin D therapy in individuals at high risk of hypertension. It was a double-blind, multicenter, randomized controlled trial.
Participants (n=38) were derived from the Vitamin D Therapy in Individuals at High Risk of Hypertension Study. The original study included 534 men and women ages 18-50 years old with 25(OH)D lower than 25 ng/mL and untreated prehypertension or stage I hypertension. Participants were randomized to receive low-dose vitamin D (400 IU) or high-dose vitamin D (4,000 IU) daily for 6 months.
The current publication involved a subset of 38 randomly selected men and women who had T-cell function in whole blood measured.
Among the cohort of 38 patients for whom T-cell function was assessed, 20 participants were randomized to low-dose vitamin D and 18 participants were randomized to high-dose vitamin D. The median age was 45 years (interquartile range, 39-47 years); 9 were women (24%); 8 (21%) were white, 29 (76%) were black, and 1 (3%) was of other or unknown race. Patients were treated with vitamin D for a mean of 117 days (SD: 52 days). Per protocol, both groups were vitamin D–deficient, with similarly low baseline 25(OH)D levels (mean, 16.2 ng/mL; SD, 6.8 ng/mL).
Exclusion criteria included use of an antihypertensive medication within the preceding 3 months; vitamin D supplementation (defined as vitamin D found in a multivitamin or supplement) totaling 400 IU/d within the 3 months before enrollment; and known cardiovascular disease (defined as prior myocardial infarction, percutaneous transluminal coronary, angioplasty, coronary artery bypass, or stroke).
This study confirms that in just 2 months of therapy, significant changes were made in serum vitamin D levels.
Other exclusion criteria included history of ulcerative colitis, Crohn’s disease, celiac disease, colostomy, pancreatic enzyme deficiency, short bowel syndrome, gastric bypass, cystic fibrosis, or dumping syndrome.
Study Parameters Assessed
Activation of T cells was measured by estimating release of intracellular ATP in vitro using plant lectin phytohemagglutinin on whole blood samples of participants. Measurements were taken at baseline and after 2 months of treatment with vitamin D.
Primary Outcome Measures
Whether ATP level changes were significantly different between treatment groups
After 2 months of treatment, 25(OH)D levels significantly increased by 5.77 ng/mL among those assigned low-dose vitamin D3 and 9.77 ng/mL among those assigned high-dose vitamin D3.
Treatment with high-dose vitamin D significantly decreased intracellular CD4+ATP release (difference=95.5 ng/ml; interquartile range [IQR], –219.5 to –105.8; P<0.026). In contrast, treatment with low-dose vitamin D3 did not significantly influence intracellular CD4+ ATP release (difference=0.5 ng/mL; IQR, –69.2 to –148.5; P=0.538). The difference in follow-up ATP levels at 2 months was significantly different between the low- and high-dose vitamin D3 groups.
In a proportional odds model, treatment with high-dose vitamin D3 was more likely to decrease ATP after antigen stimulation compared to low-dose vitamin D3 (odds ratio [OR]: 3.43; 95% confidence interval [CI]: 1.06-1.11).
Eleven of the 20 patients (45%) treated with high-dose vitamin D3 were considered “responders” with significant decreases in ATP levels. Among those treated with high-dose vitamin D3, 63.5% (7/16) of men, 25% (1/4) of women, 52.9% (9/17) of white, and 48.1% (8/17) of black participants were responders.
This study did not observe a significant difference in results according to race. It did, however, find a significant difference according to sex (P, interaction<0.02). Men were more likely to have decreased ATP antigen stimulation compared to women.
This study examined the function of CD4+T cells. As a quick immunology reminder, the CD4+T cells have multiple immune functions and include TH1, TH2, TH17, and T regulator (Treg) cells. The diverse functions of T cells include activation of the innate immune system, B lymphocytes, cytotoxic T cells, and nonimmune cells.1 In addition Tregs can inhibit the action of other T cells, acting as a balance to the inflammatory immune response. Unfortunately, this study did not differentiate the subtypes of CD4+T cells. So it is impossible to know which subsets of CD4+T cells were influenced by vitamin D3 supplementation.
In clinical practice we often get the question, 'How long until my vitamin D levels will increase?' This study confirms that in just 2 months of therapy, significant changes were made in serum vitamin D levels.
In this study, vitamin D was associated with changes in cell-mediated immunity through reduction in activation (less ATP produced). This reduction in activation was significantly different in the low-dose and high-dose groups, with greater suppression of activation in the high-dose group. This suggests that high doses may provide greater immune modulation than low doses.
This study is in keeping with animal studies that have demonstrated vitamin D’s modulation of autoimmunity.2 Quelling overactive immune-mediated conditions may have far-reaching clinical implications. The story, however, is complicated. Vitamin D receptors (VDRs) are found on a variety of immune cells. These VDRs have high variability themselves, with many genotypes possible. There are also vitamin D binding proteins (VDBPs) that influence the availability of vitamin D. In short, the interplay of vitamin D on immune function is complex, and confounding the data is the influence of VDRs, VDBPs, other nutrients (eg, calcium), and hormonal influences.3
Evidence suggests that vitamin D provides an effective therapy for cell-mediated immunity-based diseases such as inflammatory bowel disease, but the ideal dosage continues to be investigated.4-6
Vitamin D may also be used as a complement to drugs established for overactive immune diseases. One study combining high-dose vitamin D with interferon β-1b in patients with multiple sclerosis showed an improvement in function and a reduction in relapse compared to patients treated with the drug alone.7
The role of vitamin D3 supplementation on immune function requires clinical trial outcomes to definitively determine if, and how much, oral vitamin D3 influences disease states. Meanwhile, it can be considered not harmful to bring our patients into the normal range of 25-hydroxycholicalciferol in an effort to optimize their health while clinical studies continue to inform us.
- Luckheeram RV, Zhou R, Verma AD, Xia B. CD4?T cells: differentiation and functions. Clin Dev Immunol. 2012;2012:925135.
- Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J. 2001 Dec;15(14):2579-2585.
- Hewison M. An update on vitamin D and human immunity. Clin Endocrinol (Oxf). 2012;76(3):315-325.
- Reich KM, Fedorak RN, Madsen K, Kroeker KI. Vitamin D improves inflammatory bowel disease outcomes: Basic science and clinical review. World J Gastroenterol. 2014;20(17):4934-4947.
- Pappa HM, Mitchell PD, Jiang H, et al. Maintenance of optimal vitamin D status in children and adolescents with inflammatory bowel disease: a randomized clinical trial comparing two regimens. J Clin Endocrinol Metab. 2014;99(9):3408-3417.
- Wingate KE, Jacobson K, Issenman R, et al. 25-Hydroxyvitamin D concentrations in children with Crohn's disease supplemented with either 2000 or 400 IU daily for 6 months: a randomized controlled study. J Pediatr. 2014;164(4):860-865.
- Soilu-Hänninen M, Aivo J, Lindström BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012 May;83(5):565-571.