22-ene-25-oxa-vitamin D: a new vitamin D analogue with profound immunosuppressive capacities.
BACKGROUND
The biologic role of 1,25-dihydroxyvitamin D(3), such as anti-inflammatory functions, reduction of cytokine production by T cells and immunoglobulin production by B cells, is well established. However, its clinical use as an immunosuppressive agent is limited because of the hypercalcemic toxicity occurring after systemic application. The purpose of this study was to investigate the immunmodulatory effects of 22-ene-25-oxa-vitamin D (ZK156979), a novel low calcemic vitamin D analogue.


METHODS
Human peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated using the Ficoll Hypaque technique, cultured for 24 h and treated with different concentrations of ZK156979 ranging from 10(-5) to 10(-10) mol L(-1) compared with 1,25-dihydroxyvitamin D(3)[10(-5)-10(-10) mol L(-1)] following phytohaemagglutinin (PHA) stimulation. Interferon gamma (IFNgamma), tumour necrosis factor alpha (TNFalpha), interleukin 1 beta (IL-1beta), interleukin 10 (IL-10) and interleukin 4 (IL-4) secretion in supernatants were measured by ELISA.


RESULTS
ZK156979 inhibited the PHA-induced Th1-response (IFNgamma and TNFalpha levels) and the macrophage-product IL-1beta in a concentration-dependent manner (10(-10)-10(-5) mol L(-1)) with the efficiency on cytokine expression compared with 1,25-dihydroxyvitamin D(3) being slightly reduced. In contrast, ZK156979 and 1,25-dihydroxyvitamin D(3) both affected the Th2 response, leading to significantly increased IL-10- and IL-4 secretion.


CONCLUSIONS
ZK156979 is a member of novel vitamin D analogues revealing prominent immunomodulatory and suppressive characteristics with distinctive inhibition of Th1-cytokines whereas the Th2 compartment is augmented, thus providing a considerable therapeutic potential in T-cell -mediated diseases.
Daniel
C
C
First Department of Internal Medicine, ZAFES, JWG University of Frankfurt/Main, Frankfurt, Germany.
Schlauch
T
T
Zügel
U
U
Steinmeyer
A
A
Radeke
H H
HH
Steinhilber
D
D
Stein
J
J
D002117:Calcitriol / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000032:analysis; D007375:Interleukin-1 / Q000276:immunology; D016753:Interleukin-10 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
C503158:22-ene-25-oxavitamin D; D016207:Cytokines; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014807:Vitamin D; D015847:Interleukin-4; D007371:Interferon-gamma; D002117:Calcitriol