1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells.

1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is an immunomodulatory agent inducing dendritic cells (DCs) to become tolerogenic. To further understand its mechanisms of action, we have examined the effects of 1,25(OH)(2)D(3) on tolerogenic properties of blood myeloid (M-DCs) and plasmacytoid (P-DCs) human DC subsets. Exposure of M-DCs to 1,25(OH)(2)D(3) up-regulated production of CCL22, a chemokine attracting regulatory T cells, whereas production of CCL17, the other CCR4 ligand, was reduced.

Vitamin D receptor agonists, cancer and the immune system: an intricate relationship.

Vitamin D receptor (VDR) agonists can inhibit cell growth, promote apoptosis, and induce differentiation of many cell types, in addition to inhibiting metastasis and angiogenesis, all desirable properties for a drug to control cancer. However, from an immunological perspective, the immunomodulatory properties of VDR agonists are apparently just opposite to the main aims of cancer immunotherapy: boosting the immune response and breaking tumor-related tolerance. While it may be possible to identify VDR agonists with enhanced anti-proliferative/pro-differentiative and reduced immunomodulatory activities as anti-cancer agents, a complementary approach could rely on identifying clinical indications where their systemic immunomodulatory properties could be minimized.

Prevention of chronic allograft rejection by Vitamin D receptor agonists.

While immunosuppressive drugs now permit a good control of acute allograft rejection, chronic rejection remains an important unmet medical problem. We propose that Vitamin D receptor (VDR) agonists, secosteroid hormones that control cell proliferation and differentiation and exert immunoregulatory activities, in addition to regulate calcium and bone metabolism, have the potential to contribute to the management of chronic allograft rejection. Recent advances in understanding the immunomodulatory and growth-regulating properties of VDR agonists indicate the clinical applicability of these hormones in transplantation, with the aim of facilitating tolerance induction and preventing chronic graft rejection.

Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3.

1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is a secosteroid hormone that renders dendritic cells (DCs) tolerogenic, favoring the induction of regulatory T cells. Induction of DCs with tolerogenic properties by 1,25(OH)(2)D(3) is associated with increased selective expression of immunoglobulin-like transcript 3 (ILT3), suggesting its involvement in the immunoregulatory properties of this hormone. Here we show an in vivo correlate of the increased ILT3 expression on DCs in healing psoriatic lesions following topical treatment with the 1,25(OH)(2)D(3) analog calcipotriol.

Inhibition of acute and chronic allograft rejection in mouse models by BXL-628, a nonhypercalcemic vitamin D receptor agonist.

Background: Vitamin D receptor (VDR) agonists are immunomodulatory agents that have been shown to prolong allograft survival in several transplantation models, but calcemic liability remains an issue.

Methods: To study the effect of VDR agonists on acute rejection, the authors have used the heterotopic vascularized heart model, and to assess their long-term effects, the aortic allograft model, which shows immune-mediated intimal thickening similar to the vascular lesions of human chronic allograft rejection. VDR agonists were administered orally from days -1 to 30, or until allografts were rejected.

Suppressive effect of 1alpha,25-dihydroxyvitamin D3 on type I IFN-mediated monocyte differentiation into dendritic cells: impairment of functional activities and chemotaxis.

Dendritic cells (DCs) generated by a single-step exposure of human monocytes to type I IFN and GM-CSF (IFN-DCs) are endowed with potent immunostimulatory activities and a distinctive migratory response to specific chemokines. In this study, we evaluated the effects of 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active metabolite of vitamin D(3), on the DC differentiation/activation induced by type I IFN. We found that 1,25(OH)(2)D(3) prevented the generation of IFN-DCs when added to freshly isolated monocytes, and was capable of redirecting already differentiated IFN-DCs toward a more immature stage, as revealed by their immunophenotype, reduced allostimulatory activity, and impaired LPS-induced production of Th1-polarizing cytokines.

A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development.

Type 1 diabetes (T1D) is an autoimmune disease characterized by leukocyte infiltration into the pancreatic islets, and we have previously shown that treatment of adult NOD mice with a vitamin D analog arrests the progression of insulitis, blocks Th1 cell infiltration into the pancreas, and markedly reduces T1D development, suggesting inhibition of chemokine production by islet cells. In this study, we show that all TLRs are expressed by mouse and human islet cells, and their engagement by pathogen-derived ligands markedly enhances proinflammatory chemokine production. The vitamin D analog significantly down-regulates in vitro and in vivo proinflammatory chemokine production by islet cells, inhibiting T cell recruitment into the pancreatic islets and T1D development.

Dendritic cells as key targets for immunomodulation by Vitamin D receptor ligands.

Vitamin D receptor (VDR) ligands, in addition to controlling calcium metabolism, exert important effects on the growth and differentiation of many cell types and possess pronounced pro-tolerogenic immunoregulatory activities. VDR ligands can act directly on T cells, but antigen-presenting cells (APCs), and in particular dendritic cells (DCs), appear to be primary targets for their tolerogenic properties. The capacity of VDR ligands to target APCs and T cells is mediated by VDR expression in both cell types and by the presence of common targets in their signal transduction pathways, such as the nuclear factor NF-kB that is down-regulated in APCs and in T cells.

Oxidative stress stimulates IL-4 and IL-6 production in mast cells by an APE/Ref-1-dependent pathway.

Mast cells are exposed to an oxidative environment in the course of allergic and inflammatory reactions. We have examined the effects of H(2)O(2) stimulation in a primary rat basophilic leukemia cell line (RBL-2H3) and compared with IgE-dependent stimulation. Like IgE stimulation, H(2)O(2) up-regulates IL-4 and IL-6 gene expression and cytokine secretion, shows a little effect on IL-5 but does not induce IL-10 gene expression.