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- Title
A Nonsecosteroidal Vitamin D Receptor Modulator Ameliorates Experimental Autoimmune Encephalomyelitis without Causing Hypercalcemia.
- Authors
Songqing Na; Yanfei Ma; Jingyong Zhao; Schmidt, Clint; Qing Q. Zeng; Chandrasekhar, Srinivasan; Chin, William W.; Nagpal, Sunil
- Abstract
Vitamin D receptor (VDR) agonists are currently the agents of choice for the treatment of psoriasis, a skin inflammatory indication that is believed to involve an autoimmune component. 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active metabolite of vitamin D, has shown efficacy in animal autoimmune disease models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and type I diabetes. However, the side effect of 1,25-(OH)2D3 and its synthetic secosteroidal analogs is hypercalcemia, which is a major impediment in their clinical development for autoimmune diseases. Hypercalcemia develops as a result of the action of VDR agonists on the intestine. Here, we describe the identification of a VDR modulator (VDRM) compound A that was transcriptionally less active in intestinal cells and as a result exhibited less calcemic activity in vivo than 1,25-(OH)2D3. Cytokine analysis indicated that the VDRM not only modulated the T-helper cell balance from Th1 to Th2 effector function but also inhibited Th17 differentiation. Finally, we demonstrate that the oral administration of compound A inhibited the induction and progress of experimental autoimmune encephalomyelitis in mice without causing hypercalcemia.
- Subjects
VITAMIN D; ENCEPHALOMYELITIS; AUTOIMMUNE diseases; T cell receptors; HYPERCALCEMIA; TYPE 1 diabetes; ANIMAL models in research
- Publication
Autoimmune Diseases (2090-0422), 2011, p1
- ISSN
2090-0422
- Publication type
Article
- DOI
10.4061/2011/132958