**7. Animal studies – vitamin D and type 1 diabetes**

Insulitis can be inhibited by the administration of high doses of vitamin D in NOD mice (Mathieu et al., 1992), and 1,25(OH)2D3 can prevent autoimmune diabetes in these animals (Mathieu et al., 1994). In both spontaneously developing and cyclophosphamide induced models of diabetes mellitus, vitamin D protects against autoimmune diabetes in NOD mice through restoration of the deficient suppressor cell function (Mathieu et al., 1995). VDR ligands enhance CD4+CD25+ regulatory T cells; these cells may play a role in protecting against insulitis in NOD mice (Adorini, 2003).

The loss of balance between the Th1 cells and Th2 cells, with the overproduction of the Th1 cells, appears to be central in the autoimmune diabetes pathogenesis. In NOD mice, the exposure to GAD65 leads to T cell proliferation and antibody production (Kaufman et al., 1993), at the same time as insulitis develops. 1,25 dihydroxyvitamin D3 administration leads to a local immune shift of the balance between the Th1 cells and Th2 cells, favoring the increase in IL-4 production and the decrease in the interferon secretion.

Inhibition of mitogen-stimulated T-cell cultures by vitamin D has been also reported (Rigby

On the other hand, suppressor T cells are stimulated by vitamin D, leading to the inhibition

While inhibiting the IL-12 production from the DC, vitamin D is able to shift the differentiation of T naïve cells into Th0 cells and further into Th2 cells (IL-12 is an important cytokine that preferentially promotes the Th1 cell formation from the Th0 cells) (Willheim et

A recent study reported the direct modulation of CD4+ T cell function by active vitamin D, describing the inhibition of IL-17, IL-21, IFN, and the induction of T reg cells expressing CTLA-4 and FoxP3. If the T cells are grown in an environment rich in IL-2 and vitamin D, they express the highest levels of CTLA-4 and FoxP3, and are able to suppress the

VDR is normally expressed on the B cells only upon their activation. Chen reported that 1,25 (OH)2D3 decreased B cell proliferation and immunoglobulin production and induced

Vitamin D inhibits the production of inflammatory interleukins: IL-12, IL-2, interferon , tumor necrosis factor (TNF)-α, and TNF-β ,while the production of anti-inflammatory cytokines (IL-4, IL-10, TGF-β) is stimulated. This may disrupt the production of Th1 cells, which are destructive for the pancreatic beta cells, with a resultant beneficial effect on the

1α,25 (OH)2 D3 appears to have a direct protective effect against pancreatic beta cell destruction by reducing the expression of MHC class I molecules (Hahn et al, 1997). In addition, vitamin D appears to increase islet cell expression of the A20 protein, which has antiapoptotic function (Riachy et al., 2002) (Fig 2). Vitamin D also decreases the expression of Fas, which is a transmembrane cell surface receptor mediator, involved in pancreatic beta

Insulitis can be inhibited by the administration of high doses of vitamin D in NOD mice (Mathieu et al., 1992), and 1,25(OH)2D3 can prevent autoimmune diabetes in these animals (Mathieu et al., 1994). In both spontaneously developing and cyclophosphamide induced models of diabetes mellitus, vitamin D protects against autoimmune diabetes in NOD mice through restoration of the deficient suppressor cell function (Mathieu et al., 1995). VDR ligands enhance CD4+CD25+ regulatory T cells; these cells may play a role in protecting

The loss of balance between the Th1 cells and Th2 cells, with the overproduction of the Th1 cells, appears to be central in the autoimmune diabetes pathogenesis. In NOD mice, the exposure to GAD65 leads to T cell proliferation and antibody production (Kaufman et al., 1993), at the same time as insulitis develops. 1,25 dihydroxyvitamin D3 administration leads to a local immune shift of the balance between the Th1 cells and Th2 cells, favoring the

increase in IL-4 production and the decrease in the interferon secretion.

et al., 1984)

al., 1999).

cell death (Chen et al., 2007).

cell apoptosis (Riachy et al., 2006).

of T-cell mediated immunity (Mathieu et al., 1994).

proliferation of the resting CD4+ T cells (Jeffery et al., 2009).

beta cells (Lemire, 1995, van Etten & Mathieu 2005).

**7. Animal studies – vitamin D and type 1 diabetes** 

against insulitis in NOD mice (Adorini, 2003).

**6.2 Vitamin D and type 1 diabetes: Direct effects on pancreatic cells** 

Overbergh et al demonstrated that in NOD mice the immune shift between Th1/Th2 cells occurs in the periphery and is not limited to the pancreas (Overbergh et al., 2000). Furthermore, this change in the immune milieu occurs only in the autoantigen–specific immune response (exposure to GAD65, insulin B-chain, heat shock protein 65), and is not observed in the immune response associated with other antigens (ovalbumin, tetanus toxins, etc).

The recurrence of autoimmune diabetes mellitus after islet cell transplant was prevented in NOD mice by treatment with vitamin D analogs in combination with cyclosporine A (Casteels et al., 1998). Further, the administration of a nonhypercalcemic vitamin D analog in combination with an immunosuppressant (cyclosporine A) prevented progression to overt diabetes mellitus, even after the insulitis developed (Casteels et al., 1998). This effect, however, could not be reproduced when the vitamin D analog was administered without the addition of cyclosporine.

The NOD mice have an increased resistance to apoptosis in their immune cells. 1,25 dihydroxyvitamin D3 restores apoptosis in NOD mice in the thymus, leading to the increased destruction of autoimmune effector cells (Casteels et al., 1998).

In the BB rat, another animal model for autoimmune diabetes mellitus, 1,25 dihydroxyvitamin D did not lead to any significant difference in the incidence of diabetes when given from weaning to 120 days (Mathieu et al., 1997). This finding illustrates the issue of potentially different disease mechanisms in various animals and the difficulty of applying research findings from one animal model to another, or to humans.
