22‐ene‐25‐oxa‐vitamin D: a new vitamin D analogue with profound immunosuppressive capacities

Daniel, Carolin; Schlauch, T; Zügel, Ulrich; Steinmeyer, Andreas; Radeke, Heinfried H.; Steinhilber, Dieter; Stein, J.

doi:10.1111/j.1365-2362.2005.01492.x

Cited by 17 publications

(10 citation statements)

References 57 publications

(67 reference statements)

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“…These data confirm our recent in vitro findings with this analog in phytohemagglutinin-stimulated human PBMCs (Daniel et al, 2005). The substantial amelioration of the clinical parameters of Th1-mediated TNBS-induced colitis was accompanied by a significant down-regulation of the inflammatory response as assessed by MPO activity and local TNF-␣ and IFN-␥ levels.…”

Section: Discussionsupporting

confidence: 80%

“…In a previous in vitro study using human PBMCs, we clearly demonstrated prominent immunosuppressive capabilities for ZK156979, resulting in strong inhibition of the phytohemagglutinin-induced Th1-response (IFN-␥ and TNF-␣), as well as of the macrophage-product IL-1␤ with a molar potency on cytokine expression being only marginally reduced compared with that of calcitriol (Daniel et al, 2005). In addition, in these in vitro experiments ZK156979, in concordance with calcitriol, also affected the Th2 response, leading to significant increases of IL-4 and IL-10.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we showed that one representative compound, 22-ene-25-oxa vitamin D (ZK156979) (Fig. 1), may qualify as a promising member of this novel class of vitamin D analogs since it revealed prominent immunomodulatory and suppressive characteristics in vitro in human peripheral blood mononuclear cells (PBMCs) with inhibition of Th1 cytokines whereas the Th2 compartment was augmented (Daniel et al, 2005).…”

mentioning

confidence: 99%

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The New Low Calcemic Vitamin D Analog 22-Ene-25-Oxa-Vitamin D Prominently Ameliorates T Helper Cell Type 1-Mediated Colitis in Mice

Daniel¹,

Radeke²,

Sartory³

et al. 2006

J Pharmacol Exp Ther

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In addition to its well defined role as a key regulator of calcium and bone metabolism, 1,25-dihydroxyvitamin D 3 (calcitriol) has been established as a potent modulator of immune cell function. Still, because of the hypercalcemic toxicity occurring after systemic application of the parent compound, its clinical application as an immunosuppressant has been hampered. Recently, we described 22-ene-25-oxa-vitamin D (ZK156979) as a representative of a novel class of low calcemic vitamin D analogs with well preserved immunosuppressive activity in vitro. Here, in vivo colitis was induced by applying a rectal enema of 2,4,6-trinitrobenzene sulfonic acid (TNBS) to male BALB/c mice, and calcitriol (0.2 g/kg) or ZK156979 (0

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The New Low Calcemic Vitamin D Analog 22-Ene-25-Oxa-Vitamin D Prominently Ameliorates T Helper Cell Type 1-Mediated Colitis in Mice

Daniel¹,

Radeke²,

Sartory³

et al. 2006

J Pharmacol Exp Ther

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“…Extending two previous investigations (Daniel et al, 2005(Daniel et al, , 2006, the data of this in vivo study in an accepted model of Th1-mediated colitis in mice clearly indicates and unravels that combining dexamethasone with calcitriol represents an attractive new immune modulatory treatment regimen of inflammatory disorders, including CD. To our knowledge, here we show for the first time that the complex immunemodulating effects of calcitriol may result from a differential down-regulation of proinflammatory capacities of intestinal DC as assessed by analysis of IL-12p70 as well as IL-23p19.…”

Section: Discussionmentioning

confidence: 95%

Immune Modulatory Treatment of Trinitrobenzene Sulfonic Acid Colitis with Calcitriol Is Associated with a Change of a T Helper (Th) 1/Th17 to a Th2 and Regulatory T Cell Profile

Daniel

Sartory²,

Zahn³

et al. 2007

J Pharmacol Exp Ther

419

307

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A number of recent studies testify that calcitriol alone or in combination with corticosteroids exerts strong immune modulatory activity. As a new approach, we evaluated the protolerogenic potential of calcitriol and dexamethasone in acute T helper (Th)1-mediated colitis in mice. A rectal enema of trinitrobenzene sulfonic acid (TNBS) (100 mg/kg) was applied to BALB/c mice. Calcitriol and/or dexamethasone were administered i.p. from days 0 to 3 or 3 to 5 following the instillation of the haptenating agent. Assessment of colitis severity was performed daily. Colon tissue was analyzed macroscopically and microscopically, and myeloperoxidase activity, as well as cytokine levels [tumor necrosis factor-␣, interferon-␥, interleukin (IL)-12p70, IL-1␤, IL-10, IL-4] were determined by enzymelinked immunosorbent assay, T-bet, GATA family of transcription factors 3, a Th2 master regulator (GATA3), Foxp3, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), IL-23p19 and IL-17 expression by immunoblot analysis. The combination of the steroids most effectively reduced the clinical and histopathologic severity of TNBS colitis. Th1-related parameters were down-regulated, whereas Th2 markers like IL-4 and GATA3 were up-regulated. Apart from known steroid effects, calcitriol in particular promoted regulatory T cell profiles as indicated by a marked increase of IL-10, TGF␤, FoxP3, and CTLA4. Furthermore, analysis of dendritic cell mediators responsible for a proinflammatory differentiation of T cells revealed a significant reduction of IL-12p70 and IL23p19 as well as IL-6 and IL-17. Thus, our data support a rationale for a steroid-sparing, clinical application of calcitriol derivatives in inflammatory bowel disease. Furthermore they suggest that early markers of inflammatory dendritic cell and Th17 differentiation qualify as new target molecules for both calcitriol and highly selective immune-modulating vitamin D analogs.Calcitriol has been identified in a number of studies as a prominent negative regulator of T helper (Th1)-type immune responses, whereas Th2 responses are not affected or even augmented as indicated by an induction of T1/ST2 (Schmitz et al., 2005;Wang et al., 2005). Although these effects have been preferentially explained by direct effects on lymphocytes, subsequent studies clearly supported a role of calcitriol in modulating monocyte differentiation or dendritic cell (DC) maturation (Griffin et al., 2003). Calcitriol clearly reduced the transition of the innate immune stimulation to an adaptive inflammatory immune response by interfering with signal transducers and activators of transcription, interferon regulatory factor 1/4, and possibly with the molecular elements involved in cross-presentation (Penna and Adorini, 2000;Muthian et al., 2006). With respect to myeloid DC development, the phenotype of calcitriol-conditioned DC reflects an immature status with poor capacity to induce antigen-specific T cell proliferation and a tendency to promote tolerance in vivo (Mellman and Steinman, 2001).The immunoregu...

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“…However, our data should be validated by investigation of a larger study cohort, because of the limited group size. The reports on vitamin D-mediated modulation of T-helper cell polarization in mice and human are heterogeneous (Hayes et al, 2003) and include altered Th1/IFN-g (Daniel et al, 2005), Th2/IL-4 (Hayes et al, 2003), but also tolerogenic responses (Schleithoff et al, 2006;Adorini and Penna, 2008). In this study, we observed a stable recall T-helper cell response on vitamin D regarding the secretion of TT-specific or polyclonally induced IL-2, IL-4, IL-5, IL-10, IFN-g or tumor necrosis factor-a compared with placebo.…”

Section: Discussionmentioning

confidence: 99%

Efficient tetanus toxoid immunization on vitamin D supplementation

et al. 2011

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Background/Objectives: Vitamin D mediates immunomodulatory functions, and its deficiency has been associated with an increased prevalence of immunological diseases. The supplementation of vitamin D might be therapeutically beneficial, for example, in lupus erythematosus patients. However, its affect on established recall immune responses is undefined. Subjects/Methods: In all, 32 individuals were randomized in a placebo controlled, double-blind setting, and received vitamin D (daily 2000 IU) for 10 weeks followed by tetanus toxoid (TT) booster immunization. Results: During vitamin D supplementation the median 25-hydroxyvitamin D serum concentration increased to 80.3 nM, which as expected decreased in the placebo group to 29.1 nM during the ultraviolet-deprived winter months. The TT-specific immunoglobulin G (IgG) boost efficiency was marginal higher in the vitamin D group (P ¼ 0.04). The increase of the 25-hydroxyvitamin D levels correlated with the increase of TT-IgG serum concentrations. The induction of specific serum IgA and specific antibody secreting cells was comparable between both groups. Accordingly, the TT-specific and polyclonally triggered T-cell cytokine profiles were stable as well. Conclusions: Vitamin D supplementation was successful and booster immunization induced efficiently specific antibodies titers.

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22‐ene‐25‐oxa‐vitamin D: a new vitamin D analogue with profound immunosuppressive capacities

Abstract: 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.

Cited by 17 publications

References 57 publications

The New Low Calcemic Vitamin D Analog 22-Ene-25-Oxa-Vitamin D Prominently Ameliorates T Helper Cell Type 1-Mediated Colitis in Mice

The New Low Calcemic Vitamin D Analog 22-Ene-25-Oxa-Vitamin D Prominently Ameliorates T Helper Cell Type 1-Mediated Colitis in Mice

Immune Modulatory Treatment of Trinitrobenzene Sulfonic Acid Colitis with Calcitriol Is Associated with a Change of a T Helper (Th) 1/Th17 to a Th2 and Regulatory T Cell Profile

Efficient tetanus toxoid immunization on vitamin D supplementation

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