Femke Baeke

Vitamin D: modulator of the immune system

1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, is known to regulate calcium and phosphorus metabolism, thus being a key-player in bone-formation. However 1,25(OH)(2)D(3) also has a physiological role beyond its well-known role in skeletal homeostasis. Here, we describe 1,25(OH)(2)D(3) as an immunomodulator targeting various immune cells, including monocytes, macrophages, dendritic cells (DCs), as well as T-lymphocytes and B-lymphocytes, hence modulating both innate and adaptive immune responses. Besides being targets, immune cells express vitamin D-activating enzymes, allowing local conversion of inactive vitamin D into 1,25(OH)(2)D(3) within the immune system. Taken together, these data indicate that 1,25(OH)(2)D(3) plays a role in maintenance of immune homeostasis. Several epidemiological studies have linked inadequate vitamin D levels to a higher susceptibility of immune-mediated disorders, including chronic infections and autoimmune diseases. This review will discuss the complex immune-regulatory effects of 1,25(OH)(2)D(3) on immune cells as well as its role in infectious and autoimmune diseases, more in particular in tuberculosis and type 1 diabetes (T1D).

High doses of vitamin d to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial

BACKGROUND Low serum 25-hydroxyvitamin D (25-[OH]D) levels have been associated with lower FEV(1), impaired immunologic control, and increased airway inflammation. Because many patients with chronic obstructive pulmonary disease (COPD) have vitamin D deficiency, effects of vitamin D supplementation may extend beyond preventing osteoporosis. OBJECTIVE To explore whether supplementation with high doses of vitamin D could reduce the incidence of COPD exacerbations. DESIGN Randomized, single-center, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00666367) SETTING University Hospitals Leuven, Leuven, Belgium. PATIENTS 182 patients with moderate to very severe COPD and a history of recent exacerbations. INTERVENTION 100,000 IU of vitamin D supplementation or placebo every 4 weeks for 1 year. MEASUREMENTS The primary outcome was time to first exacerbation. Secondary outcomes were exacerbation rate, time to first hospitalization, time to second exacerbation, FEV(1), quality of life, and death. RESULTS Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group (mean between-group difference, 30 ng/mL [95% CI, 27 to 33 ng/mL]; P < 0.001). The median time to first exacerbation did not significantly differ between the groups (hazard ratio, 1.1 [CI, 0.82 to 1.56]; P = 0.41), nor did exacerbation rates, FEV(1), hospitalization, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) at baseline showed a significant reduction in exacerbations in the vitamin D group (rate ratio, 0.57 [CI, 0.33 to 0.98]; P = 0.042). LIMITATION This was a single-center study with a small sample size. CONCLUSION High-dose vitamin D supplementation in a sample of patients with COPD did not reduce the incidence of exacerbations. In participants with severe vitamin D deficiency at baseline, supplementation may reduce exacerbations. PRIMARY FUNDING SOURCE Applied Biomedical Research Program, Agency for Innovation by Science and Technology (IWT-TBM).

Human T lymphocytes are direct targets of 1,25-dihydroxyvitamin D3 in the immune system

Besides its actions on minerals and bone, the bioactive vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has important immunomodulatory properties. Within the immune system, dendritic cells represent key targets for this hormone and 1,25(OH)2D3-induced changes in their phenotype and function ultimately affects T lymphocytes. However, the presence of vitamin D receptors (VDR) in activated T cells proposes additional mechanisms for 1,25(OH)2D3 to directly regulate T cell responses. Here, we investigated the expression and kinetics of vitamin D-related genes in human activated T lymphocytes. Different activation stimuli elicited increased VDR- and 1-alpha-hydroxylase expression, with a highly similar kinetic pattern. Addition of 1,25(OH)2D3 effectively triggered VDR signaling, as evidenced by 24-hydroxylase induction, but only when introduced to T lymphocytes expressing high levels of VDR. This enhanced degree of VDR signaling correlated with a stronger inhibition of cytokines (IFN-gamma, IL-10) and modulation of homing receptor expression (CCR10, CLA) in long-term T cell cultures. Importantly, chronic 1,25(OH)2D3-exposure further amplified VDR signaling and the concomitant T cell modulating effects. In conclusion, we validate T cells as direct targets for 1,25(OH)2D3 and provide this optimized in vitro model to improve our understanding of the role of vitamin D as a direct regulator of T cell responses.

The Vitamin D Analog, TX527, Promotes a Human CD4+CD25highCD127low Regulatory T Cell Profile and Induces a Migratory Signature Specific for Homing to Sites of Inflammation

The use of hypocalcemic vitamin D analogs is an appealing strategy to exploit the immunomodulatory actions of active vitamin D in vivo while circumventing its calcemic side effects. The functional modulation of dendritic cells by these molecules is regarded as the key mechanism underlying their ability to regulate T cell reactivity. In this article, we demonstrate the capacity of the vitamin D analog, TX527, to target T cells directly. Microarray analysis of purified human CD3+ T cells, cultured in the presence of TX527, revealed differential expression of genes involved in T cell activation, proliferation, differentiation, and migratory capacity. Accordingly, functional analysis showed a TX527-mediated suppression of the T cell proliferative capacity and activation status, accompanied by decreased expression of effector cytokines (IFN-γ, IL-4, and IL-17). Furthermore, TX527 triggered the emergence of CD4+CD25highCD127low regulatory T cells featuring elevated levels of IL-10, CTLA-4, and OX40 and the functional capacity to suppress activation and proliferation of effector T cells. Moreover, the vitamin D analog profoundly altered the homing receptor profile of T cells and their migration toward chemokine ligands. Remarkably, TX527 not only modulated skin-homing receptors as illustrated for the parent compound, but also reduced the expression of lymphoid organ-homing receptors (CD62L, CCR7, and CXCR4) and uniquely promoted surface expression of inflammatory homing receptors (CCR5, CXCR3, and CXCR6) on T cells. We conclude that TX527 directly affects human T cell function, thereby inhibiting effector T cell reactivity while inducing regulatory T cell characteristics, and imprints them with a specific homing signature favoring migration to sites of inflammation.

Vitamin D signaling in immune-mediated disorders: Evolving insights and therapeutic opportunities

1,25(OH)(2)D(3), the active form of vitamin D, is a central player in calcium and bone metabolism. More recently, important immunomodulatory effects have been attributed to this hormone. The widespread presence of the vitamin D receptor (VDR) in the immune system and the expression of the enzymes responsible for the synthesis of the active 1,25(OH)(2)D(3) regulated by specific immune signals, even suggest a paracrine immunomodulatory role for 1,25(OH)(2)D(3). Additionally, the different molecular mechanisms used by 1,25(OH)(2)D(3) to exert its immunomodulatory effects prove of a broad action radius for this compound. Both, the effects of vitamin D deficiency and/or absence of the VDR as well as intervention with pharmacological doses of 1,25(OH)(2)D(3) or one of its less-calcemic analogs, affects immune system behavior in different animal models of immune-mediated disorders, such as type 1 diabetes. This review aims to summarize the data as they stand at the present time on the role of vitamin D in the pathogenesis of immune-mediated disorders, with special focus on type 1 diabetes, and on the therapeutic opportunities for vitamin D in the prevention and treatment of this autoimmune disease in mouse models and humans.

Vitamin D insufficiency: implications for the immune system

Chronic kidney disease (CKD) is characterized by a loss of kidney function and dysregulation of vitamin D metabolism. Well known are the defects in final activation of vitamin D to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], resulting in renal osteodystrophy. However, in recent years, 1,25(OH)2D3 has been identified as having effects far beyond calcium and bone metabolism. In this review, specific attention is given to the effects of 1,25(OH)2D3 on the immune system and the implications of vitamin D deficiency, a feature of many patients with CKD, on immune function.

Vitamin D3 and the immune system: maintaining the balance in health and disease.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D3, is a central player in Ca and bone metabolism. More recently, important immunomodulatory effects have been attributed to this hormone. By binding to its receptor, the vitamin D receptor, 1,25(OH)2D3 regulates the expression of various genes and consequently affects the behaviour of different cell types within the immune system. 1,25(OH)2D3 can potently inhibit pathogenic T cells and gives rise to elevated numbers of regulatory T cells via the induction of tolerogenic dendritic cells. These immunomodulatory activities of 1,25(OH)2D3 have also been proven useful in vivo: administration of 1,25(OH)2D3 in several animal models can prevent or cure different autoimmune diseases and graft rejection. To overcome the dose-limiting side effects of 1,25(OH)2D3 on Ca and bone, less calcaemic structural analogues (alone or in combination with synergistically acting drugs or bone-resorption inhibitors) have been successfully used in animal models. Furthermore, as 1,25(OH)2D3 also contributes to host defence against infectious agents by the induction of antimicrobial responses, this molecule might provide a new strategy to deal with drug-resistant infections. According to the pleiotropic effects of 1,25(OH)2D3 in the immune system, increasing epidemiological data underline the importance of adequate vitamin D intakes in reducing the risk of several autoimmune diseases and infections such as tuberculosis.

Dietary supplementation with high doses of regular vitamin D3 safely reduces diabetes incidence in nod mice when given early and long-term

High doses of the active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], prevent diabetes in the NOD mouse but also elicit unwanted calcemic side effects. Because immune cells themselves can convert vitamin D3 into 1,25(OH)2D3 locally, we hypothesized that dietary vitamin D3 can also prevent disease. Thus, we evaluated whether dietary administration of high doses of regular vitamin D3 (800 IU/day) during different periods of life (pregnancy and lactation, early life [3–14 weeks of age], or lifelong [3–35 weeks of age]) safely prevents diabetes in NOD mice. We found that only lifelong treatment raised serum 25-hydroxyvitamin D3 from 173 nmol/L in controls to 290 nmol/L, without inducing signs of calcemic or bone toxicity, and significantly reduced diabetes development in both male and female NOD mice. This diabetes protection by vitamin D3 correlated with preserved pancreatic insulin content and improved insulitis scores. Moreover, vitamin D3 treatment decreased interferon-γ–positive CD8+ T cells and increased CD4+(CD25+)FoxP3+ T cells in pancreatic draining lymph nodes. In conclusion, this study shows for the first time that high doses of regular dietary vitamin D3 can safely prevent diabetes in NOD mice when administered lifelong, although caution is warranted with regards to administering equivalently high doses in humans.

Crucial Role of Interferon-γ in Experimental Autoimmune Prostatitis

PURPOSE An autoimmune etiology is proposed in some patients with chronic nonbacterial prostatitis since they show interferon-gamma secreting lymphocytes specific to prostate antigens in the periphery and increased interferon-gamma in seminal plasma. We investigated the involvement of interferon-gamma in an animal model of autoimmune prostatitis. MATERIALS AND METHODS Experimental autoimmune prostatitis was studied in the no-obese diabetic and C57Bl/6 (Harlan, Zeist, The Netherlands) susceptible mouse strains, and in the IRF-1 KO and STAT-1 KO mouse strains deficient in transcription factors involved in interferon-gamma signaling. RESULTS Experimental autoimmune prostatitis was characterized by prostate specific interferon-gamma secreting cells in the periphery and by T-helper 1 related cytokines in the target organ. Increased interferon-gamma and interleukin-12 were observed in the prostate of autoimmune animals while interleukin-10 and interleukin-4 were decreased and unaltered, respectively. The absence of transcription factors involved in the interferon-gamma signaling cascade, IRF-1 and STAT-1, made mice resistant to experimental autoimmune prostatitis. IRF-1 KO and STAT-1 KO mice immunized with prostate antigens did not show infiltration or alterations in the prostate. They did not have the typical prostate specific autoimmune response and showed decreased interferon-gamma, interleukin-12 and interleukin-10, and augmented interleukin-4 in the prostate. CONCLUSIONS Our results argue for a crucial role of interferon-gamma as a key factor in the pathogenesis of the disease. Intense research is promptly required to identify the pathogenic mechanisms underlying chronic prostatitis/chronic pelvic pain syndrome to find a more rational therapy.