Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3

Abstract

1,25 dihydroxyvitamin D3, the active form of vitamin D, has immunomodulatory properties in vitro and in vivo. We report that treatment with 1,25 dihydroxyvitamin D3 (5 micrograms/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 dihydroxy-vitamin D3 resulted in a complete normalisation of the capacity to induce suppressor mechanisms in an autologous MLR, which is severely depressed in control NOD mice. The existence of such suppressor cells was confirmed in transfer experiments, whereby cotransfer of splenocytes from 1,25 dihydroxyvitamin D3 treated NOD mice prevented diabetes transfer by splenocytes from diabetic NOD mice into irradiated, 6-8-week-old male NOD mice. Other known immune defects of the NOD mice, such as defective natural killer cell killing of YAC-1 targets and defective thymocyte activation by anti-CD3 were not corrected. The pharmacological doses of 1,25 dihydroxyvitamin D3 were universally 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 control group, p < 0.005), whereas osteocalcin levels nearly doubled and bone calcium content was halved. These findings show that 1,25 dihydroxyvitamin D3 can prevent diabetes in NOD mice, probably through the correction of their defective suppressor function.

Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring

“…Similarly, the doses in studies on NOD mice, in which a protective association was reported, were pharmacological; in addition vitamin D was administered in the form of the bioactive hormone, i.e. 1,25-dihydroxyvitamin D3 or its analogues [4][5][6][7].…”

“…In studies with NOD mice, lack of vitamin D at an early age has been found to increase the later risk of autoimmune diabetes [3,4]. In several NOD mice studies, pharmacological doses of bioactive vitamin D in the form of 1,25-dihydroxyvitamin D 3 or its analogues were seen to protect from autoimmune diabetes [4][5][6][7] and other autoimmune diseases [8]. Vitamin D has several effects on the immune system that could be of relevance in the pathogenesis of type 1 diabetes [8,9].…”

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

“…It is noteworthy that the pattern of cytokine/ chemokine expression was similar in both male and female NOD mice, except for a late induction of IL-15 in males. Male and female NOD mice develop peripheral insulitis at the same age, but beta-cell destruction and diabetes mellitus are more prevalent in female NOD mice [4,5,63]. This suggests that increased chemokine expression has a more important role in the recruitment and homing of immune cells than in the later phase of destructive insulitis.…”

Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice

“…In different animal models of autoimmune diseases administration of high doses of 1,25(OH) 2 D 3 is able to prevent disease [8,9,10,11,12] and in recent years both T lymphocytes and antigen presenting cells, especially dendritic cells, have been identified as main targets for 1,25(OH) 2 D 3 in the immune system [13].…”