A Novel Immunosuppressive 1α,25-Dihydroxyvitamin D3 Analog with Reduced Hypercalcemic Activity

Abstract

1Alpha,25-dihydroxyvitamin D3, the biologically active form of vitamin D3, is a potent immunomodulatory molecule; however, its clinical use as an immunosuppressant is limited due to its strong effects on calcium homeostasis and the risk of associated side-effects. Here, we present a representative of a novel class of vitamin D analogs that exhibits potent immunosuppressive activity in a murine model of contact hypersensitivity when applied systemically and is efficacious also at nonhypercalcemic dosages. In vitro analysis revealed a binding affinity of ZK 191784 to the vitamin D receptor comparable with 1,25-dihydroxyvitamin D3. This compound inhibits lymphocyte proliferation and secretion of tumor necrosis factor alpha and interleukin-12 in monocytes in a concentration-dependent manner, but with reduced potency and efficacy than 1,25-dihydroxy-vitamin D3. Treatment of human monocytes with this analog significantly reduces expression of major histocompatibility complex class II, B7.1, and intercellular adhesion molecule-1 equipotent to 1,25-dihydroxyvitamin D3. Interestingly, the compound failed to induce vitamin D-induced differentiation of human promyelocytic leukemia cell line HL-60 to monocytes and was capable of antagonizing the action of 1,25-dihydroxyvitamin D3. In vivo, as analyzed in mice the compound potently inhibits the contact hypersensitivity when applied systemically. ZK 191784 has a clear therapeutic advantage over 1,25-dihydroxyvitamin D3 by inducing immunosuppressive effects also at concentrations that do not cause hypercalcemia. ZK 191784 is the first representative of a novel class of vitamin D analogs that might have therapeutic potential in T cell-mediated immune disorders.

Calcitriol analog ZK191784 ameliorates acute and chronic dextran sodium sulfate-induced colitis by modulation of intestinal dendritic cell numbers and phenotype

“…9; P < 0.05). As demonstrated previously [26] , the calcitriol compound did not increase serum levels of calcium in a significant manner, as compared to serum calcium levels in control animals (data not shown).…”

“…However, calcitriol has clear dose-limiting hypercalcemic effects that interfere with its systemic clinical use due to strong influence on calcium homeostasis and the risk of associated side effects. Recently, ZK191784, a new low-calcemic calcitriol derivative, has been identified that inhibits lymphocyte proliferation and suppresses secretion of proinflammatory cytokines by monocytes [26] . The compound has shown immunosuppressive activity in a murine contact hypersensitivity model when given systemically at concentrations that do not cause hypercalcemic effects, thereby suggesting a possible therapeutic application as an immunosuppressive agent [26] .…”

“…Recently, ZK191784, a new low-calcemic calcitriol derivative, has been identified that inhibits lymphocyte proliferation and suppresses secretion of proinflammatory cytokines by monocytes [26] . The compound has shown immunosuppressive activity in a murine contact hypersensitivity model when given systemically at concentrations that do not cause hypercalcemic effects, thereby suggesting a possible therapeutic application as an immunosuppressive agent [26] . The aim of our study was to investigate whether this modified calcitriol analog might have potential therapeutic value in the treatment of acute and chronic intestinal inflammation, using the DSS model of colitis.…”

“…T he calcitriol analog ZK191784 was synthesized as previously described [26] , dissolved in ethanol at a concentration of 1 × 10 -2 mol/L and kept at -20℃ until use. The following antibodies were used in the study (all purchased from BD Pharmingen, Heidelberg, Germany): anti-CD3, anti-CD11c, anti-CD28, anti-CD16/CD32, anti-MHC-Ⅱ, anti-CD40, anti-CD80, and anti-CD86.…”

Osteopontin

“…17,18 Besides other properties, calcitriol has profound effects on immunoregulation and its analog ZK 191784 has an immunosuppressive impact. 19,20 The aim of the present study was to investigate the contribution of OPN to remodeling processes in enterovirusinduced myocarditis and subsequent DCM. We used the murine model of CVB3-induced myocarditis, in which susceptible A.BY/SnJ mice develop chronic myocarditis and severe cardiac fibrosis following acute infection resulting from a restricted type of virus persistence, whereas resistant C57BL/6 mice eliminate the virus during acute infection without evolving significant fibrosis.…”