OH 2D3 in Animal Models of Immune-Mediated Diseases

In EAE l,25(OH)2D3 is clearly therapeutically effective since it entirely protects mice from disease and it may block disease progression [107, 131]. Using VDR agonists in a chronic relapsing EAE model, protection from relapses was achieved when VDR agonists were administered at disease onset or after the first peak of the disease [132]. Similar results were found in rat EAE and were associated with an inhibition of CD4 (on APCs rather than on T cells), MHC class II, CDllb/c and NOS II expression in relevant areas of the CNS [133, 134]. l,25(OH)2D3 did not protect VDR-deficient mice against EAE [107] showing the VDR dependence and specificity of the effect. 

Clear disease protection through l,25(OH)2D3 has been shown in the NOD mouse model of type I diabetes since vitamin D deficiency almost doubles the incidence of diabetes in female mice to 88% and induces diabetes in almost 50% of male mice. Diabetes was prevented by dietary administration of 50 ng of 1,25 (OH)2D3/day [135, 136]. A variety of additional studies in the NOD mouse model led to the l,25(OH)2D3-sensitive role of Thl-type Tcells and CD4+CD25+ Tregs (see 

Models of rheumatoid arthritis (RA) were object to l,25(OH)2D3 treatment, providing additional support for the high potential of the hormone for the treatment of Thl-mediated diseases. As an example, in rat adjuvant arthritis l,25(OH)2D3 improved the inhibiting effect of cyclosporine A on arthritis onset as well as on arthritis aggravation [142]. The incidence and severity of type II collagen-induced arthritis was reduced in rats or mice orally treated with 25-(OH)2-D3, the 1,25 (OH)2D3 analog MC 1288 or l,25(OH)2D3 [143-145], l,25(OH)2D3 has further proven to be therapeutically effective in animal models of autoimmune thyroiditis [146], allogeneic transplantation [66, 147,148], rat Heymann nephritis [149] and autoimmune prostatitis [80]. Results from l,25(OH)2D3-related studies in animal models are summarized in Table 10.3. 

Results from clinical studies were, however, partly unexpected regarding the large and virtually uniform in vitro findings. No significant changes of immune parameters (CD2, CD19, CD4 and CD8) were noted in a study where alfacalcidol was administered to hemodialyzed patients over 6 months only NK cell numbers were increased 

25-Dihydroxyvitamin D3 and its Dissociated Analogs as Modulators of Vitamin D Receptor Action 

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