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* Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; and
BioXell, Milano, Italy
Experimental autoimmune uveitis (EAU) serves as a model for human autoimmune uveitis and for cell-mediated autoimmunity in general. EAU induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein in CFA is driven by the Th17 response. Oral calcitriol (1,25-dihydroxyvitamin D3) prevented as well as partly reversed disease and suppressed immunological responses. In vitro, calcitriol directly suppressed IL-17 induction in purified naive CD4+ T cells without inhibiting Th17 lineage commitment, as reflected by unaltered ROR
t, STAT3, and FoxP3 expression. In contrast, in vivo treatment with calcitriol of mice challenged for EAU impaired commitment to the Th17 lineage, as judged by reduction of both RORt and IL-17 in CD4+ T cells. Innate immune response parameters in draining lymph nodes of treated mice were suppressed, as was production of IL-1, IL-6, TNF-
, and IL-12/IL-23p40, but not IL-10, by explanted splenic dendritic cells (DC). Finally, supernatants of calcitriol-conditioned bone marrow-derived DC had reduced ability to support Th17 polarization of naive CD4+ T cells in vitro and in vivo. Thus, calcitriol appears to suppress autoimmunity by inhibiting the Th17 response at several levels, including the ability of DC to support priming of Th17 cells, the ability of CD4+ T cells to commit to the Th17 lineage, and the ability of committed Th17 T cells to produce IL-17.
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1 This work was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health.
2 Current address: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Avenue S., A4203 MCN, Nashville, TN 37232.
3 Current address: Ophthalmology, University Eye Hospital Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany.
4 Current address: Institute of Inflammation and Immune Diseases, Shantou University Medical College, 22 Xin Ling Road, Shantou City, 515041, People’s Republic of China.
5 Current address: Intercept Pharmaceuticals, Via Togliatti 22bis, Corciano (Perugia), 06073, Italy.
6 Address correspondence and reprint requests to Dr. Rachel R. Caspi, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Building 10, Room 10N222, 10 Center Drive, National Institutes of Health, Bethesda, MD 20892-1857. E-mail address: rcaspi{at}helix.nih.gov
7 Abbreviations used in this paper: VDR, vitamin D receptor; BMDC, bone marrow-derived dendritic cell; CT, cycle threshold; DC, dendritic cell; DTH, delayed-type hypersensitivity; EAU, experimental autoimmune uveitis; IRBP, interphotoreceptor retinoid-binding protein; KO, knockout; LN, lymph node; Treg, T regulatory.
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