Immunomodulatory role of 1,25‐dihydroxyvitamin D₃

Abstract

The active vitamin D metabolite 1,25-dihydroxyvitamin D3 [1,25-D3] is thought to promote many of its actions through interaction with a specific intracellular receptor. The discovery of such receptors in monocytes and activated lymphocytes has led investigators to evaluate the role of the hormone on the immune system. The sterol inhibits lymphocyte proliferation and immunoglobulin production in a dose-dependent fashion. At a molecular level, 1,25-D3 inhibits the accumulation of mRNA for IL-2, IFN-gamma, and GM-CSF. At a cellular level, the hormone interferes with T helper cell (Th) function, reducing Th-induction of immunoglobulin production by B cells and inhibiting the passive transfer of cellular immunity by Th-clones in vivo. The sterol promotes suppressor cell activity and inhibits the generation of cytotoxic and NK cells. Class II antigen expression on lymphocytes and monocytes is also affected by the hormone. When given in vivo, 1,25-D3 has been particularly effective in the prevention of autoimmune diseases such as experimental autoimmune encephalomyelitis and murine lupus but its efficacy has been limited by its hypercalcemic effect. Synthetic vitamin D3 analogues showing excellent 1,25-D3-receptor binding but less pronounced hypercalcemic effects in vivo have recently enhanced the immunosuppressive properties of the hormone in autoimmunity and transplantation.

Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis

“…Several studies have shown that 1,25-dihydroxyvitamin D 3 inhibits lymphocyte activation and dendritic cell maturation in addition to affecting other players of the immune system, such as cytokine and immunglobulin production and MHC class II expression. [22][23][24][25][26][27]52 In animal models the development of diabetes mellitus and encephalomyelitis can be prevented by the administration of 1,25-dihydroxyvitamin D 3 . 29,30 In this study, we provide evidence for an association of the BsmI and TaqI VDR polymorphisms in German patients with PBC.…”

“…18-21 1,25-dihydroxyvitamin D 3 leads to the decreased production of a number of cytokines, including IL-1, IL-2, IL-6, and IL-12, as well as TNF-␣ and -␤, and interferon gamma. [22][23][24][25][26][27] Apart from decreasing cytokine production, 1,25-dihydroxyvitamin D 3 is believed to act primarily by increasing anti-inflammatory cytokines such as IL-4 and transforming growth factor ␤. 28 A role of the VDR in autoimmune disease has been suggested experimentally in animal models.…”

Genetics of type 1 diabetes mellitus

“…20,219 There is also increasing evidence of the key role of vitamin D levels in T1D susceptibility. [220][221][222] Vitamin D has important immunomodulatory properties 223 and depletion or relative resistance may play a part in the aetiology of both T1DM and T2DM, possibly through effects on insulin secretion. 224 It has been shown that allelic variations in the vitamin D receptor (VDR) gene is a significant determinant of the amount of VDR mRNA and VDR protein expressed, 225 and may also affect plasma concentrations of 1,25(OH) 2 D 3 , and the response to oral vitamin D. 226 An association between VDR polymorphisms and T1DM has been reported in South Indian, German and Taiwanese populations, [227][228][229] although not necessarily with the same VDR polymorphisms.…”

Effect of vitamin D treatment in chronic GVHD

“…Interestingly, 50% of the patients receiving vit D were put off on immunosuppresion for 6 months after In vitro data indicate that vit D inhibits DC-dependent T-cell activation, T-cell proliferation, and decreases the production of type-1 helper cells cytokines IL-2, IFN-g and TNF-a, thus displaying a very potent immunomodulatory effect. 6,7 Previous reports describe the efficacy of a vit D analog MC1288 in preventing acute GVHD in a rat BM transplant model, 8 as well as the relationship between vit D receptor gene polymorphism, and acute and cGVHD. 9 The effects of vit D are mediated by the nuclear vit-D receptor.…”