Unaltered Diabetes Presentation in NOD Mice Lacking the Vitamin D Receptor

摘要

OBJECTIVE-Vitamin D deficiency increases risk for type 1 diabetes in genetically predisposed individuals, while high doses of 1,25-dihydroxyvitamin D_3 [1,25(OH)_2D_3] prevent insulitis and diabetes in NOD mice. RESEARCH DESIGN AND METHODS-Since 1,25(OH)_2D_3, regulates gene transcription through the vitamin D receptor (VDR), we investigated the role of VDR in diabetes development by creating NOD mice without functional VDR. RESULTS-VDR~(-/-) NOD mice are rachitic and have lower numbers of putative regulator cells [TCR-α/β~+CD4~- CD8~- (natural killer T-cells) and CD4~+ CD25~+ T-cells [in central and peripheral immune organs compared with VDR~(+/+) NOD litter-mates. Lipopolysaccharide-stimulated VDR~(-/-) NOD macro-phages expressed lower interleukin (IL)-1, IL-6, and CC chemokine ligand 2 mRNA, correlating with less nuclear trans-location of p65 nuclear factor-KB compared with VDR~(+/+) NOD macrophages. Thymic and lymph node dendritic cells from VDR~(-/-) NOD mice displayed an even less mature CDllc+CD86+ phenotype than VDR~(+/+) NOD mice. Despite this immune pheno-type linked to diabetes in NOD mice, VDR~(-/-) NOD mice developed insulitis and diabetes at the same rate and incidence as VDR~(+/+) NOD littermates. CONCLUSIONS-Despite aggravating known immune abnormalities in NOD mice, disruption of VDR does not alter disease presentation in NOD mice in contrast to the more aggressive diabetes presentation in vitamin D- deficient NOD mice.