Unaltered Diabetes Presentation in NOD Mice Lacking the Vitamin D Receptor

Abstract

OBJECTIVE— Vitamin D deficiency increases risk for type 1 diabetes in genetically predisposed individuals, while high doses of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] prevent insulitis and diabetes in NOD mice.

RESEARCH DESIGN AND METHODS— Since 1,25(OH)₂D₃ 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 littermates. Lipopolysaccharide-stimulated VDR^−/− NOD macrophages expressed lower interleukin (IL)-1, IL-6, and CC chemokine ligand 2 mRNA, correlating with less nuclear translocation of p65 nuclear factor-κB compared with VDR^+/+ NOD macrophages. Thymic and lymph node dendritic cells from VDR^−/− NOD mice displayed an even less mature CD11c⁺CD86⁺ phenotype than VDR^+/+ NOD mice. Despite this immune phenotype 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.