UNALTERED DIABETES PRESENTATION IN NOD MICE LACKING THE VITAMIN D RECEPTOR

Abstract

Objective: Vitamin D deficiency increases the risk for type 1 diabetes in genetically-predisposed individuals, while high doses of 1,25-dihydroxyvitamin D₃ prevent insulitis and diabetes in NOD mice.

Research Design and Methods: Since 1,25-dihydroxyvitamin D₃ 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- NKT and CD4+CD25+ T cells) in central and peripheral immune organs compared to VDR +/+ NOD littermates. LPS-stimulated VDR −/− NOD macrophages expressed lower IL-1, IL-6 and CCL2 mRNA, correlating with less nuclear translocation of p65 NF-κB, compared to 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.