PREVENTION OF AUTOIMMUNE DIABETES IN NOD MICE BY 1,25-DIHYDROXYVITAMIN-D-3

1,25 dihydroxyvitamin D-3, the active form of vitamin D, has immunomod ulatory properties in vitro and in vivo. We report that treatment with 1,25 dihydroxyvitamin D-3 (5 mu g/kg on alternate days) prevents the development of clinical diabetes in NOD mice, an animal model of human autoimmune diabetes. Diabetes incidence in female NOD mice at the age of 200 days was reduced to 8% in the 1,25 dihydroxyvitamin D treated group vs 56% in the control group (p < 0.0001). In parallel, treatment with 1,25 dihydroxyvitamin D-3 resulted in a complete normalisation o f the capacity to induce suppressor mechanisms in an autologous MLR, w hich is severely depressed in control NOD mice. The existence of such suppressor cells was confirmed in transfer experiments, whereby cotran sfer of splenocytes from 1,25 dihydroxyvitamin D-3 treated NOD mice pr evented diabetes transfer by splenocytes from diabetic NOD mice into i rradiated, 6-8-week-old male NOD mice. Other known immune defects of t he NOD mice, such as defective natural killer cell killing of YAC-1 ta rgets and defective thymocyte activation by anti-CD3 were not correcte d. The pharmacological doses of 1,25 dihydroxyvitamin D-3 were univers ally well tolerated as reflected by a normal weight gain of the mice. Serum calcium was increased (2.5+/-0.2 vs 2.2+/-0.2 mmol/l in the cont rol group, p < 0.005),whereas osteocalcin levels nearly doubled and bo ne calcium content was halved. These findings show that 1,25 dihydroxy vitamin D-3 can prevent diabetes in NOD mice, probably through the cor rection of their defective suppresser function.