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This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tang, J. Articles by Caspi, R. PubMed Articles by Tang, J. Articles by Caspi, R.

Beneficial effects of Vitamin D receptor agonists on retinal autoimmunity

¹ LI, NEI, NIH, 9000 Rockville Pike, Bethesda, MD, 20892, ² Bioxell Inc, Ntley, BioXell Inc, Nutley, NJ, Nutley, NJ, 07110, ³ Bioxell Inc, S.P.A., Via Olgettina, 58, Milano, 20132, Italy

Abstract

1,25-Dihydroxyvitamin D3 (calcitriol) is a seco-steroid hormone of multiple bioactivities that regulates the differentiation, growth and function of a broad range of cells, including cells of the immune system, by binding to the nuclear Vitamin D receptor (VDR). BXL-35 is a synthetic analog of calcitriol with reduced effects on calcium metabolism. We examined their ability to inhibit experimental autoimmune uveoretinitis (EAU), an autoimmune disease mediated by Th1/Th17-type response, which serves as a model for human posterior uveitis. B10.RIII mice were immunized with an uveitogenic regimen of 8 µg IRBP in CFA and treated orally with calcitriol or with BXL-35, throughout (prevention) or starting 7 days after EAU induction (reversal). Calcitriol at 0.5 µg/kg and BXL-35 at 10 µg/kg prevented EAU and reduced Ag specific IFN- and IL-17 production by primed lymph node cells. In addition, BXL-35 but not calcitriol was able to reverse EAU at sub-toxic doses. Mechanistic studies revealed that dendritic cells from mice treated with calcitriol had reduced production of IL-1, TNF-, IL-6 and

IL-12/23p40. Furthermore, calcitriol directly inhibited the ability of purified CD4+T cells to produce IL-17 in response to CD3/CD28 engagement under conditions favoring Th17 polarization. In contrast, calcitriol had no effect on the ability of T cells to adhere to endothelial cell monolayers. Our study suggests that the protective effects of VDR agonists on retinal autoimmunity involve direct and indirect inhibition of priming and function of autopathogenic T cells.

This Article Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tang, J. Articles by Caspi, R. PubMed Articles by Tang, J. Articles by Caspi, R.