Immunomodulation by a novel, dissociated Vitamin D₃ analogue

Abstract

The biologically active metabolite of vitamin D3, 1alpha,25-dihydroxyvitamin D3, has potent immunomodulatory activity; however, its clinical use is limited because of its hypercalcaemic activity in anti-inflammatory active doses. Here, we present ZK203278, a novel, structurally different vitamin D3 analogue with profound immunomodulatory activities. It potently inhibits lymphocyte proliferation in the mixed lymphocyte reaction, and release of cytokines that are central in inflammation, such as TNFalpha and IL-12 in the low nanomolar range. Similarly, expression of cell-surface molecules involved in cell adhesion and antigen presentation, e.g. to T cells, is down-regulated on human monocytes by low nanomolar concentrations of ZK203278. Potent anti-inflammatory activity has been demonstrated also in vivo in rodent disease models. ZK203278 inhibited allergic contact dermatitis in rodents after oral administration in doses approximately two orders of magnitude below the hypercalcaemic threshold dose. Moreover, ZK203278 significantly prolonged skin allograft survival in rats in well-tolerated doses. Altogether ZK203278, in contrast to 1alpha,25-dihydroxyvitamin D3, exerts considerable immunomodulatory activity at non-hypercalcaemic dosages and may have therapeutic potential for immune disorders or transplant rejection.

Vitamin D Receptor, Retinoid X Receptor, Ki-67, Survivin, and Ezrin Expression in Canine Osteosarcoma

“…Vitamin D in particular has been the subject of intensive research, both in its mechanism of action and its effects on various human neoplasms [6, 7, 11, 18, 23–25]. Multiple studies have demonstrated that vitamin D can affect the rate of proliferation, degree of apoptosis, and the phenotype of numerous neoplastic cell lines.…”

Vitamin D3: a helpful immuno-modulator

“…To achieve such concentrations in vivo requires supra‐physiological doses of 1,25(OH) 2 D3, which are associated with the undesired risk of hypercalcaemia. Consequently, novel therapeutic strategies point toward vitamin D analogues that do not induce hypercalcaemia, 142 which may exert considerable immunomodulatory activity at non‐hypercalcaemic dosages and may have therapeutic potential for immune disorders or transplant rejection. In patients with Crohn’s disease a vitamin D analogue activates VDR in PBMCs, affecting proliferation and exerting an immunosuppressive effect on tumour necrosis factor‐α production, which is mediated by NF‐κB down‐regulation 143 .…”

Targeting the vitamin D receptor inhibits the B cell‐dependent allergic immune response

“…Here, we analyzed the impact of a recently described low‐calcemic VDR agonist (14) on the activation of different B cell subsets. Our results show that VDR activation inhibits IgE and IgG, but also IgA to a lesser extent.…”