Vitamin D signaling in immune-mediated disorders: Evolving insights and therapeutic opportunities

Molecular Aspects of Medicine 29 (2008) 376–387

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Molecular Aspects of Medicine journal homepage: www.elsevier.com/locate/mam

Review

Vitamin D signaling in immune-mediated disorders: Evolving insights and therapeutic opportunities Femke Baeke, Evelyne van Etten, Conny Gysemans, Lut Overbergh, Chantal Mathieu * Laboratory for Experimental Medicine and Endocrinology (Legendo), Katholieke Universiteit Leuven, Leuven, Belgium

a r t i c l e

i n f o

Article history: Received 14 May 2008 Accepted 20 May 2008 Available online xxxx

Keywords: Vitamin D 1, 25(OH)2D3 Vitamin D deficiency Vitamin D receptor polymorphism Type 1 diabetes NOD mouse Prevention Autoimmunity

a b s t r a c t 1,25(OH)2D3, the active form of vitamin D, is a central player in calcium and bone metabolism. More recently, important immunomodulatory effects have been attributed to this hormone. The widespread presence of the vitamin D receptor (VDR) in the immune system and the expression of the enzymes responsible for the synthesis of the active 1,25(OH)2D3 regulated by specific immune signals, even suggest a paracrine immunomodulatory role for 1,25(OH)2D3. Additionally, the different molecular mechanisms used by 1,25(OH)2D3 to exert its immunomodulatory effects prove of a broad action radius for this compound. Both, the effects of vitamin D deficiency and/or absence of the VDR as well as intervention with pharmacological doses of 1,25(OH)2D3 or one of its less-calcemic analogs, affects immune system behavior in different animal models of immune-mediated disorders, such as type 1 diabetes. This review aims to summarize the data as they stand at the present time on the role of vitamin D in the pathogenesis of immune-mediated disorders, with special focus on type 1 diabetes, and on the therapeutic opportunities for vitamin D in the prevention and treatment of this autoimmune disease in mouse models and humans. Ó 2008 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is vitamin D3 a vitamin or a hormone? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is the immune system vitamin D3-responsive? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiological role of vitamin D3 in the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutic effects of the pharmacological treatment with 1,25(OH)2D3 or its analogs on immune-mediated disorders . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Recognition, in the previous century, by the medical world of a link between the presence of immune abnormalities and a deficiency in vitamin D (Nnoaham and Clarke, 2008) and confirmation, in the last decades, by basic science researchers of the * Corresponding author. Tel.: +32 16 346023; fax: +32 16 345934. E-mail address: [email protected] (C. Mathieu). 0098-2997/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mam.2008.05.004

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expression of vitamin D receptors in multiple immune cell types (Veldman et al., 2000), has lead to scientific and clinical interest in vitamin D with respect to its role in the pathogenesis of immune-mediated disorders, but even more with respect to its therapeutic potential in the prevention and treatment of these diseases (Baeke et al., 2007; DeLuca and Cantorna, 2001; Mathieu and Adorini, 2002; Van Etten and Mathieu, 2005). Vitamin D has been validated as potent immunomodulatory agent in a plethora of immune-mediated disorders, ranging from infectious and allergic conditions to autoimmune diseases and organ transplantation, in humans as well as in animal models. As our laboratory has mainly studied the molecule and its mechanism of action in the NOD mouse, a model for autoimmune type 1 diabetes, this disease will be used as reference in the further part of the work. The autoimmune disease type 1 diabetes is characterized by the immune-mediated destruction of the insulin-producing b-cells in the islets of Langerhans in the pancreas, making patients dependent on exogenous insulin for survival. Most type 1 diabetes prevention studies have up to now been carried out in the NOD mouse, an animal model for type 1 diabetes, and can be divided in several major categories: pure immune suppression, immune modulation, (antigen-specific) tolerance induction and b-cell protection. Results in NOD mice are promising for many of these treatments, but many obstacles to human applications still exist. Studies involving long-term immune suppression are inconceivable as strategy for the prevention of a chronic disease striking mainly children. Moreover, the preliminary results of these drugs in recent-onset diabetic patients are disappointing. At this moment the major interest in the field of type 1 diabetes prevention research is focused on immune modulation and b-cell protection, two characteristics of vitamin D and its natural and synthetic metabolites. Therefore this review aims to summarize the data as they stand at the present time on the role of vitamin D in the pathogenesis of type 1 diabetes and on the therapeutic opportunities for vitamin D in the prevention and treatment of this autoimmune disease in mouse models and humans.

2. Is vitamin D3 a vitamin or a hormone? Although vitamin D3 can be obtained by nutritional uptake, UVB-mediated photosynthesis in the skin serves as the main source of this secosteroid compound (Holick, 1981, 2002). Therefore, by definition vitamin D3 is not a true vitamin. It is formed from 7-dehydrocholesterol (7DHC or pro-vitamin D3), which is present in large amounts in cell membranes of keratinocytes of the basal or spinous epidermal layers. By the action of UV-B light the B ring of 7DHC can be broken to form pre-vitamin D3, which is rapidly isomerized to vitamin D3 by thermal energy. The conformational change due to this isomerisation can deliver vitamin D3 into the circulation, where it is caught by the vitamin D binding protein (DBP) and then transported to the liver for further metabolization (Haddad et al., 1993). In general, extracellular transport of all vitamin D metabolites is a DBP-dependent process. Maintaining normal vitamin D3 levels in adults and children is generally obtained by an ‘‘efficient” sun exposure of face and hands for 2 h per week. However, in subjects at risk of deficiency or in conditions of high demand such as pregnancy, lactation and early childhood, extra food supplementation is recommended to maintain adequate vitamin D levels. Vitamin D can be obtained from dietary sources of vegetal (vitamin D2 or ergocalciferol) or animal origin (vitamin D3 or cholecalciferol). The best food sources are fatty fish or its liver oils but small amounts are also found in butter, cream and egg yolk. It is however very difficult to obtain adequate vitamin D levels solely from a natural diet (Holick, 2003). Human and cow’s milk, for example, are poor sources of vitamin D, providing only 15–70 IU/l (Hollis et al., 1981). Therefore, in North America products like fluid and dried milk, margarine’s, butter and certain cereals are routinely supplemented with vitamins D2 and D3. Regrettably, the real vitamin D content of these products is frequently quite different from the labeling standard and is often insufficient to reach the daily requirements of vitamin D. Although there is still no consensus about appropriate vitamin D levels, serum concentrations of 30–50 ng/ml 25(OH)D3 or higher are currently accepted as normal (Hollis, 2005). According to the current Dietary Reference Intakes, adequate vitamin D intake for children and younger adults is 5 lg or 200 IU/day, whereas it is 10 lg or 400 IU/day for adults between 51 and 70 years of age, and 15 lg or 600 IU/day for people older than 70 years of age (Scientific Advisory Committee on Nutrition, 2007; Standing Committee on the Scientific Evaluation of Dietary Reference Intakes FaNBIom, 1997). However, since various clinical studies revealed that an intake of 500–1000 IU of vitamin D/day is needed to maintain serum 25(OH)D3 levels of 30 ng/ml, the above recommended daily vitamin D intakes are believed to be inappropriate (Heaney et al., 2003; Meier et al., 2004; Tangpricha et al., 2003). In certain populations, such as sunlight-deprived subjects, the intake of 500–1000 IU vitamin D/day might even be insufficient to maintain these 25(OH)D3 levels (Glerup et al., 2000). Moreover, with daily intakes of 4000 IU, serum levels of 25(OH)D3 have been reported to remain within the physiological range (Grant and Holick, 2005; Vieth et al., 2001). Finally, the formulated guidelines are based on maintaining bone and mineral health and do not take into account the non-calcemic benefits of vitamin D3. Based on these and other evidences, the urgent question has been raised these last years from within the scientific community of vitamin D and nutrition researchers to consider an increase in the current recommended intake of vitamin D so as to adequately meet overall health requirements. To bring concentrations in 50% of the population up to 30 ng/ml 25(OH)D3, a daily intake of 1000 IU vitamin D as been proposed for all racial-ethnic groups (Bischoff-Ferrari et al., 2006; Vieth et al., 2007). To become biologically active, two hydroxylation steps of vitamin D3 are necessary. First 25-hydroxylation, mainly taking place in the liver and carried out by 25-hydroxylases (CYP27A1, CYP2R1, CYP3A4, and CYP2J3), gives rise to 25-hydroxyvitamin D3 (25(OH)D3). In some other tissues, like kidney, parathyroid cells and keratinocytes, 25-hydroxylase activity has also been demonstrated. This 25(OH)D3 is the main circulating form of vitamin D3 in the blood. The second hydroxylation, mainly

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taking place in the proximal tubule cells of the kidney, is performed by 1a-hydroxylase (CYP27B1) and gives rise to the active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). 1a-Hydroxylase is also expressed in other tissues like skin, bone, cartilage, prostate and macrophages, thus providing high local 1,25(OH)2D3 concentrations for autocrine and paracrine actions without affecting serum concentrations. Tissue availability of the active 1,25(OH)2D3 not only depends on adequate dietary intake and sun exposure but also on the activity of its metabolizing enzymes. Since the activity of 25-hydroxylase is poorly regulated, circulating 25(OH)D3 levels in general accurately reflect vitamin D status. By contrast, 1a-hydroxylase activity in the kidney is under strict control of calcium and phosphate and their regulating hormones (calcium, PTH, calcitonin, GH and IGF1 being positive and phosphate and FGF23 and 1,25(OH)2D3 itself being negative regulators) (reviewed in Bouillon, 2005a). Although identical to the kidney gene, the expression of 1a-hydroxylase in other tissues, thus providing high local 1,25(OH)2D3 concentrations for autocrine and paracrine actions without affecting serum concentrations, is regulated quite differently. Hence, 1a-hydroxylase expression in macrophages is significantly upregulated by immune signals such as IFNc and LPS or viral infections (Dusso et al., 1997; Esteban et al., 2004; Monkawa et al., 2000; Nguyen et al., 1997; Overbergh et al., 2000a, 2006; Stoffels et al., 2006). In dendritic cells (DC), 1a-hydroxylase expression is associated with the p38 MAPK- and NFjB-dependent maturation of these cells (Hewison et al., 2003). Importantly, and in contrast with 1a-hydroxylase regulation in kidney, neither in macrophages nor in DCs, 1a-hydroxylase activity is subjected to 1,25(OH)2D3-mediated negative feedback (Hewison et al., 2003; Overbergh et al., 2000a). Upregulation of 1a-hydroxylase, and therefore 1,25(OH)2D3 synthesis, by immune cells typically occurs at later stages of immune activation, thus providing a late negative feedback loop of 1,25(OH)2D3-mediated downregulation of immune responses. Finally, the almost ubiquitously expressed multifunctional 24-hydroxylase (CYP24A1) is responsible for the catabolism of 25OHD3 and 1,25(OH)2D3. 1,25(OH)2D3 itself is a very strong inducer of 24-hydroxylase expression by the presence of two VDRE sequences in this gene’s promoter, thus inducing its own catabolism (Chen and DeLuca, 1995). This negative feedback loop probably serves as an internal rescue to avoid excessive 1,25(OH)2D3 levels and signaling. In immune cells, such as monocytes, macrophages and DCs, this 1,25(OH)2D3-mediated negative feedback of 24-hydroxylase is however dependent on the maturation status of the cell. This is due to an inhibitory effect of the maturation-inducing IFNc signal on the 1,25(OH)2D3mediated 24-hydroxylase upregulation. IFNc-induced STAT1 interacts with the DNA-binding domain of the VDR thereby prohibiting binding of the ligand/VDR/RXR-complex to the 24-hydroxylase promoter and preventing 1,25(OH)2D3-mediated induction of the enzyme (Vidal et al., 2002). Like this, undifferentiated monocytes are highly susceptible to 1,25(OH)2D3mediated 24-hydroxylase induction, whereas differentiated/activated macrophages are resistant. In DCs, 24-hydroxylase expression was only observed when the cells underwent their differentiation process in the presence of 1,25(OH)2D3 (Hewison et al., 2003). Both, the lack of negative feedback of 1,25(OH)2D3 on its own production (1a-hydroxylase) as well as the resistance to initiate its own breakdown (24-hydroxylase) explains the massive local production of 1,25(OH)2D3 by diseaseassociated macrophages that is seen in patients with granulomatous diseases (sarcoidosis and tuberculosis) and the consequent possible spill over of 1,25(OH)2D3 in the general circulation eventually leading to systemic hypercalcemia. More recent data indicate that also other members of the immune system, such as T cells (Sigmundsdottir et al., 2007) express the enzymes responsible for the production of the active 1,25(OH)2D3 (25- and 1a-hydroxylase), again accentuating that all elements leading to the regulated presence of 1,25(OH)2D3 in the immune system are available. 3. Is the immune system vitamin D3-responsive? Vitamin D metabolites are lipophilic molecules that can easily penetrate cell membranes and translocate to the nucleus. Only 1,25(OH)2D3 is metabolically active and exerts its effects mainly by activating the nuclear vitamin D receptor (VDR) (Haussler et al., 1998). This VDR is a member of the nuclear receptor super-family of ligand-activated transcription factors, which also comprises the thyroid hormone receptor, retinoic acid receptor and peroxisome proliferator-activated receptor. Binding of 1,25(OH)2D3 to VDR triggers a sequence of events, from the induction of heterodimerization of VDR with the retinoid X receptor (RXR), and the binding of this ligand/VDR/RXR complex to vitamin D response elements (VDREs) in the promoter region of responsive genes, over the recruitment of several coactivators and corepressors, to the eventual alterations in the transcription of 1,25(OH)2D3-regulated genes. Different types of VDREs have been identified. The classical DR3-type VDRE is composed of a direct hexanucleotide repeat separated by 3 interspacing nucleotides (Umesono et al., 1991). Similar direct repeats with 4 (DR4-type) or 6 (DR6-type) interspacing nucleotides have been reported as well (Carlberg et al., 1993; Gill and Christakos, 1993; Rhodes et al., 1993). Another well documented VDRE-type is known as the IP9-type which comprises an inverted palindromic arrangement of 2 hexameric binding sites (Schrader et al., 1995). Interaction between the ligand/VDR/RXR-complex and a VDRE facilitates the assembly of the transcription initiation complex by the release of corepressors and the recruitment of nuclear receptor coactivator proteins, including members of the steroid receptor coactivator (SRC) family and the vitamin D3 receptor interacting proteins (DRIP). The recruited proteins induce chromatin remodeling through intrinsic histone-modifying activities and attract key components of the transcription initiation complex to the regulated promoters. Alternatively, when the ligand/VDR/RXR complex is recruited to an inhibitory VDRE, corepressors are recruited and gene transcription is inhibited (Dusso et al., 2005). Besides the expression of VDR in classical 1,25(OH)2D3-responsive target tissues (bone, kidney, intestine, parathyroid glands), it is expressed in a broad range of other normal and malignant cell types. The discovery that VDR is widely expressed

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in the immune system, including activated CD4+ and CD8+ T lymphocytes, antigen-presenting cells (APCs), such as macrophages and DCs, as well as B lymphocytes (the latter not always confirmed) (Provvedini et al., 1983; Veldman et al., 2000), led to the recognition of a central immunomodulatory role for 1,25(OH)2D3 (Baeke et al., 2007; Mathieu and Adorini, 2002). Here as in other 1,25(OH)2D3-responsive tissues, the 1,25(OH)2D3/VDR/RXR complex can directly interact with VDREs in the promoter region of 1,25(OH)2D3-target genes to carry out immunomodulatory effects (Table 1). Examples of this type of 1,25(OH)2D3-mediated induction of gene transcription are TNFa and cathelicidin (Hakim and Bar-Shavit, 2003; Wang et al., 2004). An example of an inhibitory VDRE was found in the promoter region of the IFNc gene (Cippitelli and Santoni, 1998). Presumably, IFNc production is inhibited by the binding of the ligand/VDR/RXR complex to this negative VDRE as well as by the interaction with a crucial upstream enhancer element. Remarkably, suppression of the expression of the granulocyte and macrophage growth factor GM-CSF by 1,25(OH)2D3 is achieved in a unique manner, i.e. by binding of ligand-bound VDR monomers to functional repressive complexes in the promoter region of this cytokine gene (Towers et al., 1999; Towers and Freedman, 1998). In the immune system, however, the mechanism by which 1,25(OH)2D3 exerts most of its effects is by interfering with the signaling pathways of other transcription factors (Table 1). The 1,25(OH)2D3/VDR/RXR complex dose-dependently interferes with the signaling of transcription factors, such as NFAT, NFjB and AP-1, that play a crucial role in regulating immunomodulatory genes and whose dysregulation is suggested to be involved in the pathogenesis of different autoimmune diseases, among which type 1 diabetes (Eggert et al., 2004). In DCs and many other cell types the NFjB pathway is a very important target in the 1,25(OH)2D3-mediated effects and 1,25(OH)2D3 interferes at different levels with this pathway: inhibition of phosphorylation (and subsequent ubiquitination and degradation) of the cytosolic inhibitor of NFjB (IjBa), inhibition of NFjB nuclear translocation, binding (and therefore retention) of NFjB to VDR in the nucleus, interference with the binding of the NFjB-complex to DNA. Moreover, a negative VDRE has been found in the promoter of the NFjB member RelB, thus contributing to the 1,25(OH)2D3-mediated inhibition of NFjB-mediated maturation of DCs (Dong et al., 2005). Constitutive association of (unliganded) VDR with the RelB promoter is enhanced by ligand-binding but decreased by LPS. This process is

Table 1 Molecular mechanisms of action of 1,25(OH)2D3 in the immune system Target gene Mechanism

Inhibitory IFNc VDRE

References

;

Jurkat T cells

Cippitelli and Santoni (1998)

;

Murine and human DCs

Dong et al. (2005)

Direct interaction of the ligand/VDR/RXR complex " with a stimulating VDRE as well as indirect effects via CD14 upregulation Cathelicidin Direct interaction of the ligand/VDR/RXR complex " with VDRE in cathelicidin promoter - in keratinocytes need for SRC3 and influence of histone acetylation

Murine bone marrow macrophages Human monocytes, macrophages, neutrophils, keratinocytes Murine macrophages Monocytes, macrophages

Hakim and Bar-Shavit (2003)

RelB

Positive VDRE

Interaction of the ligand/VDR/RXR complex with a negative VDRE and inhibition of an upstream enhancer element Constitutive association of empty VDR, increased by ligand, decreased by LPS/maturation and controlled by chromatin remodeling (HDAC3)

Effect on Cell type gene transcription

TNFa

24-OHase

No VDRE was detected in the murine cathelicidin gene " Positive effects of 1,25(OH)2D3 are counteracted by the interference of IFNc-induced STAT1 activity with ligand/VDR/RXR DNA-binding

Adams et al. (2007), Gombart et al. (2005), Liu et al. (2006), Martineau et al. (2007), Wang et al. (2004) Gombart et al. (2005) Chen and DeLuca (1995), Vidal et al. (2002)

Unusual VDRE

GM-CSF

Binding of ligand/VDR monomers to a functional repressive promoter sequence

;

Jurkat T cells

Towers et al. (1999), Towers and Freedman (1998)

NFjB

IL12p40

Inhibition of NFjB activation and binding of the transcription factor complex to its DNA-binding site

;

D’Ambrosio et al. (1998)

IL8

Inhibition of binding of NFjB factors to the IL8 promoter

;

Murine activated macrophages and DCs Fibroblasts

IL2

Inhibition of NFAT/AP-1 protein complex formation and direct association of the ligand/VDR/RXR complex with the NFAT DNA-binding site Direct interaction of the ligand-bound VDR with a NFAT DNA-binding site

;

Indirect inhibition of c-myc transcriptional activity via interaction of ligand/VDR/RXR with a noncanonical c-Myc DNA-binding site

;

NFAT/AP1

IL4 MAPK

FasL

;

Harant et al. (1998)

Jurkat T cells and Takeuchi et al. (1998) human tonsilar T lymphocytes Murine naïve CD4+ T Staeva-Vieira and Freedman (2002) lymphocytes Murine activated T hybridoma cells

Effects of 1,25(OH)2D3 on the level of target gene transcription are expressed as inhibitory (;) or stimulatory (").

Cippitelli et al. (2002)

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controlled by chromatin remodeling by means of histone deacetylase 3 activity. Other examples of signaling pathways affected by 1,25(OH)2D3 by means of which 1,25(OH)2D3 exerts its immunomodulatory effects are depicted in Table 1. This very broad range of expression of VDR and the very diverse ways 1,25(OH)2D3 uses to interfere with gene-expression, explain its very broad spectrum of activities compared to classical immunosuppressants and its pleiotropic immunomodulatory effects. Overall, the regulated expression within the immune system of all the components needed for 1,25(OH)2D3 synthesis (25-, 1a-, and 24-hydroxylase) as well as 1,25(OH)2D3 function (VDR), strongly suggests a physiological role for this substance as a messenger or cytokine-like molecule between immune cells. Therapeutic possibilities in the prevention of immune-mediated disorders, such as the autoimmune disease type 1 diabetes, are to be expected.

4. Physiological role of vitamin D3 in the immune system A strong association between vitamin D deficiency and important immune-mediated disorders has been documented in experimental animal models and human subjects. Vitamin D deficiency has been associated with an increased susceptibility to infections, with the oldest known correlation for tuberculosis (Chan, 2000; Davies et al., 1985; Nursyam et al., 2006; Waters et al., 2004). Multiple macrophage functions indispensable for antimicrobial activity, such as chemotaxis, phagocytosis and pro-inflammatory cytokine production, are defective in vitamin D-deficient mice. Moreover, the increased risk upon vitamin D deficiency for Th1-mediated autoimmune diseases, such as inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis as well as type 1 diabetes (Peterlik and Cross, 2005), suggests that the 1,25(OH)2D3-mediated attenuation of pathological Th1 immune responses is impaired under this condition. Another strong argument linking vitamin D levels to immune function is the correlation between areas with low vitamin D supply (due to insufficient sunlight exposure time or nutritional vitamin D uptake) and increased incidences of different autoimmune diseases (Cantorna and Mahon, 2004; Ponsonby et al., 2002). The seasonal variation in onset and exacerbations of autoimmune diseases, with a peak in late winter/early spring when serum vitamin D levels are lowest, strengthen this correlation (Iikuni et al., 2007). Whereas vitamin D deficiency is strongly correlated with immune abnormalities, the effects of supplements of vitamin D or 25(OH)D3 in immune-mediated disorders are less clear. Much depends on the initial vitamin D levels before supplementation: whether supplementation restores existing vitamin D deficiency or adds extra vitamin D to already vitamin D sufficient levels. The fact that not for all studies this initial vitamin D status is known, adds to this unclarity. In NOD mice, vitamin D deficiency during early life results in a more aggressive diabetes manifestation with an earlier onset and a higher incidence (Giulietti et al., 2004; Zella and DeLuca, 2003). The thymus of these mice contains decreased CD8+ T cell numbers but increased immature CD4+CD8+ T cell numbers, possibly pointing towards a T cell maturation problem. Moreover, numbers of regulatory CD4+CD62L+ T cells, already low in NOD mice, are further decreased in both thymus and peripheral lymph nodes of vitamin D deficient NOD mice. Besides these T cell abnormalities, also peritoneal macrophages of vitamin D deficient NOD mice show severe functional defects, with lower respiratory burst capacity and a disturbed cytokine profile (increased IL15 and extremely low IL1 and IL6). Their aberrant inflammatory behavior might, besides disturbing their antimicrobial activity, impair the migratory capacity of these resident macrophages, thus trapping them in the pancreas and inducing non-specific pancreatic b-cells damage eventually triggering a b-cell destructive cascade. Accordingly, excessive expression of proinflammatory cytokines, indicative of a higher activation status of the infiltrating immune cells, has been found in the islets of vitamin D deficient NOD mice, with a more aggressive disease presentation as clinical outcome. As for vitamin D supplementation, daily giving 1000 IU of regular vitamin D to already vitamin D sufficient NOD mice does not protect from autoimmune diabetes, although the insulin content in the islets of normal as well as diabetic animals is increased (Mathieu et al., 2002). The same is true for BB rats, another animal model spontaneously developing autoimmune diabetes (Mathieu et al., 2004). In humans, epidemiological data show a threefold increase in type 1 diabetes when vitamin D deficiency was present in early life (Hypponen et al., 2001). Multiple studies have moreover evaluated the impact of vitamin D intake in the first phase of life (pregnancy, infancy, childhood) on the prevalence of type 1 diabetes or diabetes-related autoimmunity. (The Eurodiab Substudy 2 Study Group, 1999; Fronczak et al., 2003; Hypponen et al., 2001; Stene et al., 2000). These studies consistently show an inverse correlation between good management of vitamin D levels and diabetes-related parameters. Also 25(OH)D3 levels at onset of disease have been found decreased (Littorin et al., 2006; Pozzilli et al., 2005). At present these data have lead to the design of an intervention study in neonates with high genetic risk for developing type 1 diabetes (Wicklow and Taback, 2006). Novel insights in the possible role of vitamin D/1,25(OH)2D3 in the pathogenesis of type 1 diabetes come from epidemiological data on correlations between VDR polymorphisms and diabetes risk in different populations. In humans, the gene encoding for VDR is located on chromosome 12cen-q12 and shows extensive polymorphism throughout the complete sequence, from the different promoter regions (Cdx2 in promoter region 1e) over exons (FokI in exon 2, TaqI in exon 9) and introns (BsmI and ApaI in intron 8) to the 30 -untranslated region (a mononucleotide [(A)n] repeat polymorphism) (Uitterlinden et al., 2004; Valdivielso and Fernandez, 2006). An association between some of these VDR gene polymorphisms and type 1 diabetes susceptibility has been shown in different populations. Mc Dermott et al. demonstrated excessive transmission of one of the BsmI alleles in South Indian subjects with type 1 diabetes, linking the VDR BsmI polymorphism to an increased risk for type 1 diabetes (McDermott et al., 1997). This association was confirmed in other populations (Chang et al., 2000; Ogunkolade et al., 2002; Pani et al., 2000; Yokota et al., 2002). Until now, no clear explanation for this association is provided. A functional implication is more apparent for the FokI polymorphism, as suggested by recent data from our group where we

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demonstrated that the FokI allele generating a shorter VDR protein induced a more active immune system (Van Etten et al., 2007b). In contrast with these correlation data, a recent meta-analysis could not find any evidence for an association between VDR gene polymorphisms and type 1 diabetes risk in either case-control or family-transmission studies (Guo et al., 2006). On the contrary, susceptibility to type 1 diabetes has recently been associated with 1a-hydroxylase gene polymorphism (Bailey et al., 2007). Another set of important data on the involvement of vitamin D in the development of type 1 diabetes comes from a recent study in NOD mice lacking functional VDR expression (Gysemans et al., 2008). Although these VDR/NOD mice do not show aggravated diabetes presentation, they show clear immune defects. A relative deficiency of different regulatory cell types (TCRa/ß+CD4-CD8-NKT cells, regulatory CD4+CD25+T cells) as well as a disturbed cytokine and chemokine profile of peritoneal macrophages, reflecting a maturational defect, is apparent in these mice. Moreover, the thymus and lymph nodes of VDR/NOD mice contain lower levels of mature CD11c+ DCs, probably contributing to a defective elimination of diabetogenic T cells. One human study reports of the association of vitamin D-dependent rickets type II with type 1 diabetes (Nguyen et al., 2006). In animal models of other immune-mediated disorders, data exist on the impact of the absence of VDR on disease presentation showing, however, apparent contradictions. Whereas different models of inflammatory bowel disease are aggravated in VDR/ mice (Froicu et al., 2003; Froicu et al., 2006; Froicu and Cantorna, 2007), these mice are less susceptible to experimentally induced autoimmune encephalomyelitis (Meehan and DeLuca, 2002) as well as experimentally induced airway inflammation and asthma (Wittke et al., 2004; Wittke et al., 2007). Overall, a discrepancy between absence of ligand (vitamin D deficiency) and absence of receptor (VDR/) is apparent as to the signaling of vitamin D in immunemediated disorders (Bouillon et al., 2008). This phenomenon is largely unexplained but different immune cell types as well as different target organs involved in the pathology of the different immune-mediated disorders may play a role. Moreover, unliganded VDR may have immunomodulatory effects on its own (Cianferotti et al., 2007). This discrepancy has also been observed for other ligand/receptor pairs of the nuclear receptor super-family of ligand-activated transcription factors (Brent, 2000).

5. Therapeutic effects of the pharmacological treatment with 1,25(OH)2D3 or its analogs on immune-mediated disorders Next to the physiological importance of vitamin D signaling in obtaining a fully operational immune system, the beneficial effects of treatment with active 1,25(OH)2D3 have been proven in vivo in multiple animal models of immune-mediated disorders (Table 2). These immunomodulatory effects seen in vivo are based on the very broad spectrum of ways (direct VDRE-mediated effects as well as indirect effects on other signaling pathways) by which 1,25(OH)2D3 interferes with gene expression in the immune system, as elaborated on in a previous section. Based hereon, a plethora of effects in the different immune cell types can be observed for 1,25(OH)2D3. In T cells, where first expression of VDR was observed, 1,25(OH)2D3 treatment inhibits proliferation and alters the cytokine expression profile. The most impressive and best studied immunomodulatory effects of 1,25(OH)2D3 are on the professional antigen-presenting cells, the dendritic cells. Multiple in vitro and in vivo studies on human and murine DCs show that 1,25(OH)2D3 can potently inhibit DC differentiation from its precursors as well as maturation by different stimuli (Gauzzi et al., 2005; Griffin et al., 2001; Penna and Adorini, 2000; van Halteren et al., 2002; van Halteren et al., 2004). This is reflected by alterations in morphology and in expression of antigen-capturing, -processing and -presentation machinery, T cell stimulatory molecules, cytokine profile, and inflammatory and lymph node homing receptors. Since DCs form the link between innate and adaptive immune responses, the effects of 1,25(OH)2D3 on DCs inevitably have extensive impact on T cell behavior, making this indirect pathway more important than the direct T cell-targeted effects of 1,25(OH)2D3. Hereby, T cell differentiation is skewed away from Th1 and the recently defined proinflammatory Th17 phenotypes towards a Th2 phenotype (Borgogni et al., 2008; Cantorna et al., 1998b; Casteels et al., 1998d; Daniel et al., 2008; Mahon et al., 2003; Mattner et al., 2000; Overbergh et al., 2000b) and the development of regulatory T cells and even T cell anergy is induced by 1,25(OH)2D3 (Gregori et al., 2002; Penna and Adorini, 2000; van Halteren et al., 2002; van Halteren et al., 2004). These in vitro effects of 1,25(OH)2D3 are seen in vivo only at very high doses, exceeding by 100-1000 fold the normal serum values, with consequent hypercalcemia, hypercalciuria, increased bone turnover and soft tissue calcification. Therefore structural analogs of 1,25(OH)2D3 have been developed with less calcemic effects but conserved or even more pronounced immunological effects as 1,25(OH)2D3 itself (Bikle, 1992; Bouillon et al., 2005b; Eelen et al., 2007; Gregori et al., 2002; Verstuyf et al., 2000b; Verstuyf et al., 2000a). Moreover, by combining 1,25(OH)2D3 or its analogs with other immunosuppressants, dose lowering can be achieved without losing immunomodulatory power. Multiple examples exist of the use of 1,25(OH)2D3 or its less calcemic analogs, alone or in combination therapy with other immunosuppressants, in animal models for the prevention and treatment of autoimmune diseases and the prolongation of graft survival (Table 2). Prevention of type 1 diabetes induction and progression in animal models and humans by pharmacological doses of 1,25(OH)2D3 and analogs Chronic administration of pharmacological doses of 1,25(OH)2D3 can reduce the incidence of both insulitis and diabetes in NOD mice. When 1,25(OH)2D3 or an analog is administered to NOD mice from the age of weaning until the end of the life, diabetes as well as insulitis, the histopathological lesion of type 1 diabetes, was reduced (Mathieu et al., 1992; Mathieu et al., 1994; Mathieu et al., 1995). Extensive immunological screening, including phenotypic analysis of major lymphocyte subsets,

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Table 2 The effects of the vitamin D system on animal models of immune-mediated disorders of the different body systems Systems

Immune-mediated disorder

interference of vitamin D system

Outcome

Cardiovascular Aorta, aorta/heart, heart transplantation

Treatment with 1,25(OH)2D3/ Reduced chronic allograft rejection, analogs in rats and mice delayed acute heart rejection, inhibition of intimal hyperplasia in aorta, prolongation of vascularized and non-vascularized allograft survival

Digestive

Treatment with 1,25(OH)2D3 in mice Vitamin D deficiency VDR/mice

Endocorine

Inflammatory bowel disease

Treatment with an analog in mice

Small bowel transplantation

Treatment with an analog in mice

Type 1 diabetes

Treatment with 1,25(OH)2D3/ Prevention of disease, inhibition of analogs in NOD mice insulitis and diabetes progression

Cantorna et al. (2000)

Aggravation of disease presentation

Casteels et al. (1998a, 1998d) Gregori et al. (2002) Mathieu et al. (1992), Mathieu et al. (1994, 1995) Giulietti et al. (2004), Zella and DeLuca, (2003) Gysemans et al. (2008) Fournier et al. (1990)

VDR/NOD mice Experimental autoimmune Treatment with 1,25(OH)2D3 in mice thyroiditis Liver transplantation Treatment with 1,25(OH)2D3 in rats Islet transplantation Treatment with 1,25(OH)2D3/ analogs in mice

No effect on disease presentation Reduced histological lesions and severity Decreased severity of acute allograft Redaelli et al. (2001) rejection Induction of allo-transplantation Casteels et al. (1998b), Gregori et al. tolerance, prevention of autoimmune (2001), Gysemans et al. (2001, 2002) recurrence after syngeneic transplantation, prevention of early xenograft failure

Bone marrow transplantation

Decreased graft-versus-host disease

Integumentary Psoriasis Skin transplantation Nervous

Amuchastegui et al. (2005), Hullett et al. (1998), Raisanen-Sokolowski et al. (1997)

Cantorna et al. (2000) Froicu et al. (2003, 2006), Froicu and Cantorna, (2007) anti-inflammatory effects - at least Daniel et al. (2006), Strauch et al., partially mediated through effects on (2007) mucosal DCs Prolonged allograft survival Johnsson and Tufveson (1994)

Colitis

Vitamin D deficiency

Immune

Amelioration of symptoms, block of disease progression Disease aggravation Disease aggravation

Reference

Treatment with an analog in rats

Treatment with 1,25(OH)2D3/ Prevention and amelioration of analogs in mice disease Treatment with an analog in Prolonged allograft survival mice

Experimental autoimmune Treatment with 1,25(OH)2D3/ Prevention of disease, attenuation of encephalomyelitis analogs in mice severity and relapses, delay of onset

Pakkala et al. (2001) Matsunaga et al. (1990) Bertolini et al. (1999)

VDR/mice

Protected from disease

Branisteanu et al. (1995, 1997); Cantorna et al. (1996), Lemire and Archer (1991), Van Etten et al. (2000, 2003, 2007a) Cantorna et al. (1996), Spach and Hayes (2005) Meehan and DeLuca (2002)

Reproductive

Prostatitis

Treatment with an analog in mice

Reduction of prostate infiltration

Penna et al. (2006)

Respiratory

Asthma

Treatment with 1,25(OH)2D3 in mice VDR/mice

Variable from protection over no effects to aggravation of disease Protection from disease

Matheu et al. (2003); Topilski et al. (2004) Wittke et al. (2004, 2007)

Skeletal

Collagen-induced arthritis

Treatment with 1,25(OH)2D3/ prevention of disease, suppression of Cantorna et al. (1998a), Larsson et al. analogs in rats and mice severity (1998)

Urinary

Heyman, Lupus, mercuric chloride-induced nephritis

Treatment with 1,25(OH)2D3/ Reduction to prevention of analogs in rats and mice proteinuria and autoantibodies, prevention of skin lesions, downregulation of serum Ab levels Treatment with 1,25(OH)2D3/ Prolonged allograft survival in rats analogs in rats and monkeys but not in monkeys

Branisteanu et al. (1993), Vendeville et al. (1995)

Treatment with 1,25(OH)2D3/ Prevention of disease analogs in mice

Koizumi et al. (1985); Lemire et al. (1992)

Kidney transplantation Systemic

Systemic lupus erythematosus

Vitamin D deficiency

Disease aggravation

Redaelli et al. (2002), Vierboom et al. (2006)

and evaluation of T cell proliferation and NK cell function, was unable to discover overwhelming changes in treated versus control mice. A major finding was however the restoration of suppressor cell function, a well-known defect of the NOD mouse, which could be demonstrated both in vitro and in vivo (Meehan et al., 1992). Question remains however whether this

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restoration of suppressor cells is the main mechanism of 1,25(OH)2D3 involved in the protection against diabetes. Since not only a protection against diabetes, but also against insulitis, was seen, interference of 1,25(OH)2D3 with the induction of autoimmunity itself was postulated. The basis of 1,25(OH)2D3-mediated diabetes protection seems to be a reshaping of the immune repertoire but also the direct b-cell protective effects of 1,25(OH)2D3 might play a major role. The reshaping of the immune system involves different aspects. First, 1,25(OH)2D3 induces a shift in T cell cytokine expression from predominantly Th1 (IL2, IFNc) in control mice to Th2 (IL4, IL10) locally in the pancreas and pancreas-draining lymph nodes of 1,25(OH)2D3- or analog-treated mice (Casteels et al., 1998b; Overbergh et al., 2000b). This shift is assumed to be antigen-specific since it occurs in response to diabetes-relevant but not -irrelevant antigens. Second, 1,25(OH)2D3 induces a better elimination of autoimmune effector cells. In NOD mice, this already happens centrally in the thymus, where treatment with 1,25(OH)2D3 restores the sensitivity of (self-reactive) T cells towards apoptosis-inducing signals (Casteels et al., 1998a; Casteels et al., 1998c). Finally, 1,25(OH)2D3 restores the defective regulator/suppressor cell activity. Not only prevention of diabetes can be achieved by 1,25(OH)2D3 treatment, also progression to clinically overt diabetes can be arrested. Casteels et al. demonstrated that if administered when active b-cell destruction is already present, which is the situation in pre-diabetic subjects in whom immune intervention is considered, some of the 1,25(OH)2D3 analogs, when combined with a short induction course of a classical immunosuppressant such as cyclosporine A (CsA), can arrest the progression of the disease (Casteels et al., 1998d; Gregori et al., 2002). The BB rat is another important spontaneous animal model for type 1 diabetes, with however major immune abnormalities, making it less appropriate as model system. In the BB rat, no influence on diabetes incidence was observed when 1,25(OH)2D3 was administered from weaning until 120 days (Mathieu et al., 1997). These findings in the BB rat again confirm the basic differences in disease pathogenesis that can be found between the two available animal models for type 1 diabetes and also indicate that caution is warranted when transferring findings from either of these models to the human situation. 6. Conclusions The widespread presence of VDR in the immune system and the expression of the enzymes responsible for the synthesis of the active 1,25(OH)2D3 regulated by specific immune signals, suggest a paracrine immunomodulatory role for 1,25(OH)2D3. Moreover, the different molecular mechanisms that 1,25(OH)2D3 uses to exert its immunomodulatory effects prove of a broad action radius for this compound. Indeed, vitamin D deficiency and/or absence of the VDR predisposes to different immune-mediated disorders. Also, interventional studies with pharmacological doses of 1,25(OH)2D3 or some of its analogs have been performed in multiple animal models of immune-mediated disorders and demonstrate prevention of disease through immune modulation. All these novel insights support the concept that there is indeed a role for 1,25(OH)2D3 in the pathogenesis of immune-mediated disorders, such as type 1 diabetes, and more importantly that there is a therapeutic opportunity for 1,25(OH)2D3 and analogs in the prevention and treatment of these immune-mediated disorders. In the search for the optimal analog of 1,25(OH)2D3 for diabetes protection in humans, a combination of b-cell protection, immune modulation and low calcemic effects is envisaged. 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