Immunomodulation by a novel, dissociated Vitamin D3analogue
| Autor: | Andreas Steinmeyer, Ekkehard May, Ulrich Zügel, Khusru Asadullah, Manfred Lehmann |
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| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | Experimental Dermatology. 18:619-627 |
| ISSN: | 1600-0625 0906-6705 |
| DOI: | 10.1111/j.1600-0625.2009.00845.x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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