A novel immunosuppressive 1α,25-dihydroxyvitamin D3 analog with reduced hypercalcemic activity

被引:40
作者
Zügel, U
Steinmeyer, A
Giesen, C
Asadullah, K
机构
[1] Schering AG, Res Labs, Res Business Area Dermatol, D-13342 Berlin, Germany
[2] Schering AG, Ctr Dermatol, D-13342 Berlin, Germany
关键词
autoimmunity; inflammation; skin; T lymphocytes;
D O I
10.1046/j.1523-1747.2002.19623.x
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
1alpha,25-Dihydroxyvitamin D-3 , the biologically active form of vitamin D-3 , 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 D-3 . 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 D-3 . 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 D-3 . 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 D-3 . 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 D-3 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.
引用
收藏
页码:1434 / 1442
页数:9
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