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Vitamin D and MS: Hayes

Professor of Biochemistry and Medical Microbiology
Department of Biochemistry
2260 Biochemical Sciences Building
433 Babcock Drive
Madison, WI 53706-1544, USA

T +1 (608) 263-6387
W Bichemistry UW-MADISON
W Department of Nutritional Sciences, University of Wisconsin Madison
W Genetics at UW-MADISON

Curriculum Vitae Colleen Elizabeth Hayes
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Colleen Hayes inducted into NMSS’S 2012 volunteer hall of fame
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PubMed: Hayes CE

Vitamin D3 Newsletter for Multiple Sclerosis Patients
December 2013
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March 2012
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October 2010
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May 2010
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Slide presentation
December 2013
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Suggestions for the MS patient seeking possible benefits of vitamin D (slide 25)
  • Request a test for 25-hydroxyvitamin-D (25-OH-D)
  • If 25-OH-D is less than 40 ng/mL (100 nmol/L), take vitamin D3 supplements for 2-3 months with your doctor’s supervision and repeat the test
  • Adults with limited sun exposure typically need 2000 IU (50 mcg)/day of vitamin D3 or more to achieve ~40 ng/mL (100 nmol/L) of 25-OH-D
    • Studies have shown that MS patients can safely take up to 10,000 IU (250 mcg)/day
  • Children with limited sun exposure typically need 1000 IU (25 mcg)/day of vitamin D3 or more to achieve ~40 ng/mL (100 nmol/L) of 25-OH-D
  • Some studies have shown vitamin D3 yields stronger immune system benefits than vitamin D2, so vitamin D3 supplements are suggested
  • On days when you get good sun exposure you don’t need to take vitamin D3

Suggestions for families of MS patients (slide 26)
  • Children and siblings of MS-affected individuals have a 30-fold increased risk of MS
  • Family members may benefit from maintaining healthy vitamin D3 levels (25-OH-D3 greater than 40 ng/mL(100 nmol/L))
  • Some people will need more supplementary vitamin D3 than others to maintain healthy vitamin D3 levels because they carry genetic risk factors for low 25-OH-D status
  • The Endocrine Society 2011 guidelines suggest that individuals at risk for vitamin D deficiency (those with little sun exposure) take vitamin D3 supplements
    • Infants (0 to 12 months): 400 to 1000 IU (10 to 25 mcg)/day
    • Children and teenagers (1 to 18 years): 600 to 1000 IU (15 to 25 mcg)/day
    • Adults (19 years and older): 1,500 to 2000 IU (37,5 to 50 mcg)/day
(Holick et al. J Clin Endocrinol Metabol 96:1911-1930, 2011)

Audio presentation
November 2011
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Questions for Dr. Colleen Hayes
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Research Interests
Dr. Hayes and her collaborators study mechanisms by which the sunlight-derived hormone 1,25-dihydroxyvitamin D3 regulates EAE, the animal model of the autoimmune, neurodegenerative disease multiple sclerosis. They were the first to propose that vitamin D might be a natural inhibitor of MS, due to the immunoregulatory functions of this steroid hormone. For the past fifteen years, her research team has been investigating the mechanisms that govern the metabolism of vitamin D3 into 1,25-dihydroxvitamin D3 in the central nervous system, and the pathways by which this hormone performs anti-inflammatory and neuroprotective functions in EAE.

Dr. Hayes received her PhD in biochemistry from the University of Michigan, and completed postdoctoral training in the Department of Pathology at Harvard Medical School. She has received a fellowship from the National Foundation March of Dimes and a Leukemia Society of America Scholar Award. Dr. Hayes currently serves on a scientific review panel for the National Multiple Sclerosis Society.

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS), with an uncertain cause. Colleen Hayes and Donald Achaeson have suggested that insufficient sunlight exposure and chronic viral infections might be unrelated environmental risk factors for MS. These risk factors may act synergistically to enable the pathogenic autoimmune response.

The prevalence of MS is highest where environmental supplies of vitamin D are lowest. Sunshine enables the production of vitamin D3 (D3) in the skin. Epidemiological studies have shown that higher vitamin D blood levels are associated with lower risk, less relapses and a slower progression of multiple sclerosis. Higher vitamin D levels can be achieved in part by increased oral intake of D3.

Current Research

Award: Research Grant
Term/Amount: 10/1/03-9/30/06; $467,660

“Vitamin D regulation of autoimmune encephalomyelitis” Understanding how a hormone is produced in the brain and spinal cord during inflammation, and how this hormone may help to resolve inflammation in an MS-like disease in mice.

A puzzling aspect of MS is that it is more common in regions of higher latitudes, such as Northern Europe, than in regions of lower latitude, such as the tropics. Colleen Hayes, PhD, believes this disparity may be caused by differences in exposure to available sunlight, and resulting vitamin D deficiencies.

In support of this idea, Dr. Hayes has marshaled evidence that vitamin D – which is created in the skin on exposure to sunlight – can lead to the production of beneficial immune messenger chemicals, or cytokines, in mice with the MS-like disease, EAE, and reverse or prevent its occurrence.

In this study, Dr. Hayes is examining how a hormone the body produces from vitamin D, called calcitriol, impacts central nervous system inflammation during the course of EAE. She has also discovered that its protective effects may be amplified by higher levels of the female sex hormone estrogen, and she is testing various dietary levels of vitamin D ingestion by male and female mice and also attempting combined therapy with estrogen.

This study will help provide important information toward understanding and maximizing any positive impact Vitamin D therapy may ultimately have on MS.

Publications Hayes CE et al.: Vitamin D and Multiple Sclerosis
Hayes CE, Donald Acheson E.
A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10.
Med Hypotheses. 2008 Apr 1

Multiple sclerosis (MS) is a neurodegenerative disease of uncertain etiology. In MS, neurodegeneration is thought to be secondary to autoimmune-mediated damage. However, no cohesive explanation yet exists as to how environmental factors interact to induce a neurodegenerative autoimmune response. Insufficient sunlight exposure and chronic viral infections have been proposed as unrelated environmental risk factors for MS. We suggest that these risk factors may act synergistically to enable the pathogenic autoimmune response. Low ultraviolet light (UVL) exposure depletes vitamin D(3) stores, and low vitamin D(3) levels correlate strongly with high MS risk. The central nervous system converts vitamin D(3) into 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), a biologically active hormone with anti-inflammatory and neuro-protective functions that depend on IL-10-producing regulatory lymphocytes. Herpesvirus infection also correlates with MS risk. Some herpesviruses like Epstein-Barr virus produce an IL-10-like cytokine termed vIL-10. We hypothesize that vIL-10 may induce a dysfunction of IL-10-producing regulatory lymphocytes, thereby undermining the protective functions of sunlight, vitamin D(3), and 1,25-(OH)(2)D(3). The vIL-10 could elicit a host immune response capable of neutralizing or depleting IL-10, or the vIL-10 could compete with IL-10 but fail to perform an essential IL-10 function.
In either case, the lack of sunlight exposure and the herpes virus infection might synergize to induce a defect in IL-10-producing regulatory lymphocyte function that undermines self-tolerance mechanisms and enables a pathogenic autoimmune response to neural proteins.

Pedersen LB, Nashold FE, Spach KM, Hayes CE.

1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking.
J Neurosci Res. 2007 Aug 15;85(11):2480-90.

Multiple sclerosis (MS) is a complex neurodegenerative disease whose pathogenesis involves genetic and environmental risk factors leading to an aberrant, neuroantigen-specific, CD4+ T cell-mediated autoimmune response. In support of the hypothesis that vitamin D3 may reduce MS risk and severity, we found that vitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) inhibited induction of experimental autoimmune encephalomyelitis (EAE), an MS model. To investigate how 1,25-(OH)2D3 could carry out anti-inflammatory functions, we administered 1,25-(OH)2D3 or a placebo to mice with EAE, and subsequently analyzed clinical disease, chemokines, inducible nitric oxide synthase (iNOS), and recruitment of dye-labeled monocytes. The 1,25-(OH)2D3 treatment significantly reduced clinical EAE severity within 3 days. Sharp declines in chemokines, inducible iNOS, and CD11b+ monocyte recruitment into the central nervous system (CNS) preceded this clinical disease abatement in the 1,25-(OH)2D3-treated animals. The 1,25-(OH)2D3 did not directly and rapidly inhibit chemokine synthesis in vivo or in vitro.
Rather, the 1,25-(OH)2D3 rapidly stimulated activated CD4+ T cell apoptosis in the CNS and spleen. Collectively, these results support a model wherein inflammation stimulates a natural anti-inflammatory feedback loop. The activated inflammatory cells produce 1,25-(OH 2D3, and this hormone subsequently enhances the apoptotic death of inflammatory CD4+ T cells, removing the driving force for continued inflammation. In this way, the sunlight-derived hormone could reduce the risk of chronic CNS inflammation and autoimmune mediated neurodegenerative disease. Copyright 2007 Wiley-Liss, Inc.

Spach KM, Nashold FE, Dittel BN, Hayes CE.

IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis.
J Immunol. 2006 Nov 1;177(9):6030-7.

Multiple sclerosis (MS) results from an aberrant, neuroantigen-specific, T cell-mediated autoimmune response. Because MS prevalence and severity decrease sharply with increasing sunlight exposure, and sunlight supports vitamin D(3) synthesis, we proposed that vitamin D(3) and 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) may protect against MS. In support of this hypothesis, 1,25-(OH)(2)D(3) strongly inhibited experimental autoimmune encephalomyelitis (EAE). This inhibition required lymphocytes other than the encephalitogenic T cells. In this study, we tested the hypothesis that 1,25-(OH)(2)D(3) might inhibit EAE through the action of IL-10-producing regulatory lymphocytes. We report that vitamin D(3) and 1,25-(OH)(2)D(3) strongly inhibited myelin oligodendrocyte peptide (MOG(35-55))-induced EAE in C57BL/6 mice, but completely failed to inhibit EAE in mice with a disrupted IL-10 or IL-10R gene. Thus, a functional IL-10-IL-10R pathway was essential for 1,25-(OH)(2)D(3) to inhibit EAE. The 1,25-(OH)(2)D(3) also failed to inhibit EAE in reciprocal, mixed bone marrow chimeras constructed by transferring IL-10-deficient bone marrow into irradiated wild-type mice and vice versa. Thus, 1,25-(OH)(2)D(3) may be enhancing an anti-inflammatory loop involving hemopoietic cell-produced IL-10 acting on brain parenchymal cells and vice versa. If this interpretation is correct, and humans have a similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and neuro-protective functions of sunlight and vitamin D(3). In this way, a genetic IL-10-IL-10R pathway defect could interact with an environmental risk factor, vitamin D(3) insufficiency, to increase MS risk and severity.
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Spach KM, Hayes CE.

Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice.
J Immunol. 2005 Sep 15;175(6):4119-26.

The prevalence of multiple sclerosis (MS) increases significantly with decreasing UV B light exposure, possibly reflecting a protective effect of vitamin D(3). Consistent with this theory, previous research has shown a strong protective effect 1,25-dihydroxyvitamin D(3) in experimental autoimmune encephalomyelitis (EAE), an MS model. However, it is not known whether the hormone precursor, vitamin D(3), has protective effects in EAE. To address this question, B10.PL mice were fed a diet with or without vitamin D(3), immunized with myelin basic protein, and studied for signs of EAE and for metabolites and transcripts of the vitamin D(3) endocrine system. The intact, vitamin D(3)-fed female mice had significantly less clinical, histopathological, and immunological signs of EAE than ovariectomized females or intact or castrated males. Correlating with reduced EAE, the intact, vitamin D(3)-fed female mice had significantly more 1,25-dihydroxyvitamin D(3) and fewer CYP24A1 transcripts, encoding the 1,25-dihydroxyvitamin D(3)-inactivating enzyme, in the spinal cord than the other groups of mice. Thus, there was an unexpected synergy between vitamin D(3) and ovarian tissue with regard to EAE inhibition. We hypothesize that an ovarian hormone inhibited CYP24A1 gene expression in the spinal cord, so the locally-produced 1,25-dihydroxyvitamin D(3) accumulated and resolved the inflammation before severe EAE developed. If humans have a similar gender
difference in vitamin D(3) metabolism in the CNS, then sunlight deprivation would increase the MS risk more significantly in women than in men, which may contribute to the unexplained higher MS incidence in women than in men.
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Spach KM, Pedersen LB, Nashold FE, Kayo T, Yandell BS, Prolla TA, Hayes CE.
Gene expression analysis suggests that 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by stimulating inflammatory cell apoptosis.
Physiol Genomics. 2004 Jul 8;18(2):141-51.

Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (CNS) that develops in genetically susceptible individuals who are exposed to undefined environmental risk factors. Epidemiological, genetic, and biological evidence suggests that insufficient vitamin D may be an MS risk factor. However, little is known about how vitamin D might be protective in MS. We hypothesized that 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] might regulate gene expression patterns in a manner that would resolve inflammation. To test this hypothesis, experimental autoimmune encephalomyelitis (EAE) was induced in mice, 1,25-(OH)2D3 or a placebo was administered, and 6 h later, DNA microarray hybridization was performed with spinal cord RNA to analyze the gene expression patterns. At this time, clinical, histopathological, and biological studies showed that the two groups did not differ in EAE disease, but changes in several 1,25-(OH)2D3-responsive genes indicated that the 1,25-(OH)2D3 had reached the CNS. Compared with normal mice, placebo-treated mice with EAE showed increased expression of many immune system genes, confirming the acute inflammation. When 1,25-(OH)2D3 was administered, several genes like glial fibrillary acidic protein and eukaryotic initiation factor 2alpha kinase 4, whose expression increased or decreased with EAE, returned to homeostatic levels. Also, two genes with pro-apoptotic functions, calpain-2 and caspase-8-associated protein, increased significantly. A terminal deoxynucleotidyl transferase-mediated dUTP nicked end labeling study detected increased nuclear fragmentation in the 1,25-(OH)2D3-treated samples, confirming increased apoptosis. Together, these results suggest that sensitization of inflammatory cells to apoptotic signals may be one mechanism by which the 1,25-(OH)2D3 resolved EAE.

Hayes CE, Nashold FE, Spach KM, Pedersen LB.
The immunological functions of the vitamin D endocrine system.
Cell Mol Biol (Noisy-le-grand). 2003 Mar;49(2):277-300. Review.

The discoveries that activated macrophages produce 1alpha25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3), and that immune system cells express the vitamin D receptor (VDR), suggested that the vitamin D endocrine system influences immune system function. In this review, we compare and contrast how 1alpha,25-(OH)2D3 synthesis and degradation is regulated in kidney cells and activated macrophages, summarize data on hormone receptor function and expression in lymphocytes and myeloid lineage cells, and discuss how locally-produced 1alpha,25-(OH)2D3 may activate a negative feed-back loop at sites of inflammation. Studies of immunity in humans and animals lacking VDR function, or lacking vitamin D, are viewed to gain insight into the immunological functions of the vitamin D endocrine system. The strong associations between poor vitamin D nutrition, particular VDR alleles, and susceptibility to chronic mycobacterial infections, together with evidence that 1alpha,25-(OH)2D3 served as a vaccine adjuvant enhancing antibody-mediated immunity, suggest a model wherein high levels of 1alpha,25-(OH)2D3-liganded VDR transcriptional activity may promote the CD4+ T helper 2 (Th2) cell-mediated and mucosal antibody responses to cutaneous antigens in vivo. We also review a diverse and rapidly growing body of epidemiological, climatological, genetic, nutritional and biological evidence indicating that the vitamin D endocrine system functions in the establishment and/or maintenance of immunological self tolerance. Studies done in animal models of multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM), inflammatory bowel disease (IBD), and transplantation support a model wherein the 1alpha,25-(OH)2D3 may augment the function of suppressor T cells that maintain self tolerance to organ-specific self antigens. The recent progress in infectious disease, autoimmunity and transplantation has stimulated a gratifying renaissance of interest in the vitamin D endocrine system and its role in immunological health.

Nashold FE, Hoag KA, Goverman J, Hayes CE.
Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis.
J Neuroimmunol. 2001 Sep 3;119(1):16-29.

Multiple sclerosis (MS) is a demyelinating disease involving genetic and environmental risk factors. Geographic, genetic, and biological evidence suggests that one environmental risk factor may be lack of vitamin D. Here, we investigated how 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) inhibits experimental autoimmune encephalomyelitis (EAE), an MS model. The experiments used adoptive transfer of TCR-transgenic (TCR1) cells specific for myelin basic protein (MBP) peptide into unprimed recipients. When unprimed TCR1 splenocytes
were transferred, and the recipients were immunized with peptide, the mock-treated mice developed EAE, but the 1,25-(OH)(2)D(3)-treated recipients remained disease-free. Both groups had TCR1 T cells that proliferated in response to MBP Ac1-11 and produced IFN-gamma but not IL-4 in the lymph node. In the central nervous system (CNS), the mock-treated mice had activated TCR1 T cells that produced IFN-gamma but not IL-4, while the 1,25-(OH)(2)D(3)-treated mice had TCR1 T cells with a non-activated phenotype that did not produce IFN-gamma or IL-4. When activated TCR1 T cells producing IFN-gamma were transferred into unprimed mice, the mock-treated and the 1,25-(OH)(2)D(3)-treated recipients developed EAE. Likewise, the 1,25-(OH)(2)D(3) did not inhibit Th1 cell IFN-gamma production or promote Th2 cell genesis or IL-4 production in vitro. Finally, the 1,25-(OH)(2)D(3) inhibited EAE in MBP-specific TCR-transgenic mice that were Rag-1(+), but not in animals that were Rag-1-null. Together, these data refute the hypothesis that the hormone inhibits Th1 cell genesis or function directly or through an action on antigen-presenting cells, or promotes Th2 cell genesis or
function. Instead, the evidence supports a model wherein the 1,25-(OH)(2)D(3) acts through a Rag-1-dependent cell to limit the occurrence of activated, autoreactive T cells in the CNS.

Nashold FE, Miller DJ, Hayes CE.
1,25-dihydroxyvitamin D3 treatment decreases macrophage accumulation in the CNS of mice with experimental autoimmune encephalomyelitis.
J Neuroimmunol. 2000 Mar 1;103(2):171-9.

Sunlight, which is required for vitamin D biosynthesis, may be protective in multiple sclerosis (MS), due to the immunoregulatory functions of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), the hormonally active vitamin D metabolite. This hypothesis provided the impetus for the experiments reported here investigating mechanisms whereby 1,25-(OH)2D3 may inhibit murine experimental autoimmune encephalomyelitis (EAE). Severe EAE was induced, 1,25-(OH)2D3 or mock treatment was administered, and clinical disease,
histopathological disease, and encephalitogenic cells in the central nervous system (CNS) were analyzed within 24-72 h of the treatment. The mock-treated mice remained paralyzed (stage 3 EAE) while most hormone-treated animals regained the partial use of both hind limbs (stage 2 EAE) within 72 h of treatment. A histopathological examination showed the hormone-treated mice had a 50% decrease
in white matter and meningeal inflammation at 72 h post treatment. A flow cytometric analysis of cell surface markers on spinal cord cells recovered 24 h post treatment showed the mock-treated mice with EAE had about 7.0 +/- 2.3 million Mac-1+ cells/cord, whereas the hormone-treated mice had about 2.1 +/- 2.6 million Mac-1+ cells/cord, which was not significantly different from the unmanipulated control mice. Otherwise, the flow cytometric analysis detected no significant differences between the groups with respect to CD4+ or CD8+ T cells
or B cells or macrophages in draining lymph nodes or spinal cords. These results are discussed with regard to possible fates for the 5 million Mac-1+ cells that were rapidly lost from the inflamed CNS in the 1,25-(OH)2D3-treated mice, and the possible beneficial effect of hormone treatment in resolving acute MS.

Hayes CE.
Vitamin D: a natural inhibitor of multiple sclerosis.
Proc Nutr Soc. 2000 Nov;59(4):531-5. Review.

Inheriting genetic risk factors for multiple sclerosis (MS) is not sufficient to cause this demyelinating disease of the central nervous system; exposure to environmental risk factors is also required. MS may be preventable if these unidentified environmental factors can be avoided. MS prevalence increases with decreasing solar radiation, suggesting that sunlight may be protective in MS. Since the vitamin D endocrine system is exquisitely responsive to sunlight, and MS prevalence is highest where environmental supplies of vitamin D are lowest, we have proposed that the hormone, 1, 25-dihydroxycholecalciferol (1,25-(OH)2D3), may protect genetically-susceptible individuals from developing MS. Evidence consistent with this hypothesis comes not only from geographic studies, but also genetic and biological studies. Over-representation of the vitamin D receptor gene b allele was found in Japanese MS patients, suggesting it may confer MS susceptibility. Fish oil is an excellent vitamin D source, and diets rich in fish may lower MS prevalence or severity. Vitamin D deficiency afflicts most MS patients, as demonstrated by their low bone mass and high fracture rates. However, the clearest evidence that vitamin D may be a natural inhibitor of MS comes from experiments with experimental autoimmune encephalomyelitis (EAE), a model of MS. Treatment of mice with 1,25-(OH)2D3 completely inhibited EAE induction and progression. The hormone stimulated the synthesis of two anti-encephalitogenic cytokines, interleukin 4 and transforming growth factor beta-1, and influenced inflammatory cell trafficking or apoptosis. If vitamin D is a natural inhibitor of MS, providing supplemental vitamin D to individuals who are at risk for MS would be advisable.

Hullett DA, Cantorna MT, Redaelli C, Humpal-Winter J, Hayes CE, Sollinger HW, Deluca HF.
Prolongation of allograft survival by 1,25-dihydroxyvitamin D3.
Transplantation. 1998 Oct 15;66(7):824-8.

BACKGROUND: 1,25-Dihydroxyvitamin D3, the hormonal form of vitamin D, is now believed to play a significant role in the immune responses, both in vitro and in vivo, preventing the development of several autoimmune diseases. These studies suggest that 1,25 dihydroxyvitamin D3 may be effective in prolonging allograph survival.
METHODS: To test the hypothesis that 1,25-dihydroxyvitamin D3 would prolong allograft survival, neonatal heart grafts were transplanted to allogeneic recipients receiving either 19-nor-1,25-dihydroxyvitamin D2 (200 ng/day) or 1,25-dihydroxyvitamin D3 (50 ng/mouse/day) orally through the diet. The efficacy of 1,25-dihydroxyvitamin D3 in prolonging graft survival in a vascularized model was determined by heterotopic ACI to Lewis heart transplants.
RESULTS: The provision of exogenous 1,25-dihydroxyvitamin D3 or an analog, 19-nor-1,25-dihydroxyvitamin D2, to mice markedly prolonged the survival of neonatal mouse heart allografts. Similar results were obtained with a vascularized heterotopic heart transplant model in rats. Cyclosporine at a maximum 25 mg/kg dose for mice proved less effective than 1,25-dihydroxyvitamin D3. Graft survival in mice differing at class I and class II loci (B10.A(4R) --> C57BL/10) increased from 13.0+/-1.1 days to 51.0+/-5.6 days and was significantly better than cyclosporine monotherapy (33.2+/-3.6). Rat heart survival in a high responder strain combination (ACI --> Lewis) increased from 6.2+/-0.3 to 25.2+/-2.8 days. The increased survival of the transplants brought about with 1,25-dihydroxyvitamin D3 was not accompanied by hypercalcemia in rats.
CONCLUSION: These results suggest that 1,25-dihydroxyvitamin D3 can be used as an effective agent in preventing graft rejection.

Cantorna MT, Woodward WD, Hayes CE, DeLuca HF.
1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4.
J Immunol. 1998 Jun 1;160(11):5314-9.

Previously we demonstrated that 1,25-dihydroxyvitamin D3 blocks the progression of relapsing encephalomyelitis. We now propose that 1,25-dihydroxyvitamin D3 blocks these autoimmune symptoms by stimulating the differentiation and/or function of cells that inhibit the encephalitogenic process. To support this belief, we have found that 1,25-dihydroxyvitamin D3 administration to mice increases IL-4 transcripts by 3- to 25-fold and TGF-beta 1 transcripts by 4- to 24-fold. Similarly, IL-4 and TGF-beta 1 transcripts were higher in the central nervous system of 1,25-dihydroxyvitamin D3-treated mice compared with controls. The number of cells recoverable from the lymph nodes of 1,25-dihydroxyvitamin D3-treated mice was only 50% that of controls. Overall, 1,25-dihydroxyvitamin D3 treatment causes a net loss in the total number of lymphocytes while the number of IL-4 and TGF-beta 1 transcripts increased. The systemic and local increase in
the expression of these two anti-inflammatory cytokines by 1,25-dihydroxyvitamin D3 may be responsible for the ability of this drug to block encephalomyelitis.
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Hayes CE, Cantorna MT, DeLuca HF.
Vitamin D and multiple sclerosis.
Proc Soc Exp Biol Med. 1997 Oct;216(1):21-7. Review.

Recently, it has been clearly demonstrated that exogenous 1,25-dihydroxyvitamin D3, the hormonal form of vitamin D3, can completely prevent experimental autoimmune encephalomyelitis (EAE), a widely accepted mouse model of human multiple sclerosis (MS). This finding has focused attention on the possible relationship of this disease to vitamin D. Although genetic traits certainly contribute to MS susceptibility, an environmental factor is also clearly involved. It is our hypothesis that one crucial environmental factor is the
degree of sunlight exposure catalyzing the production of vitamin D3 in skin, and, further, that the hormonal form of vitamin D3 is a selective immune system regulator inhibiting this autoimmune disease. Thus, under low-sunlight conditions, insufficient vitamin D3 is produced, limiting production of 1,25-dihydroxyvitamin D3, providing a risk for MS. Although the evidence that vitamin D3 is a protective environmental factor against MS is circumstantial, it is compelling. This theory can explain the striking geographic distribution of
MS, which is nearly zero in equatorial regions and increases dramatically with latitude in both hemispheres. It can also explain two peculiar geographic anomalies, one in Switzerland with high MS rates at low altitudes and low MS rates at high altitudes, and one in Norway with a high MS prevalence inland and a lower MS prevalence along the coast. Ultraviolet (UV) light intensity is higher
at high altitudes, resulting in a greater vitamin D3 synthetic rate, thereby accounting for low MS rates at higher altitudes. On the Norwegian coast, fish is consumed at high rates and fish oils are rich in vitamin D3. Further, experimental work on EAE provides strong support for the importance of vitamin D3 in reducing the risk and susceptibility for MS. If this hypothesis is correct, then 1,25-dihydroxyvitamin D3 or its analogs may have great therapeutic potential in patients with MS. More importantly, current research together with data from migration studies opens the possibility that MS may be preventable in genetically susceptible individuals with early intervention strategies that provide adequate levels of hormonally active 1,25-dihydroxyvitamin D3 or its analogs.

Cantorna MT, Hayes CE, DeLuca HF.
1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis.
Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7861-4.

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease believed to be a model for the human disease multiple sclerosis (MS). Induced by immunizing B10.PL mice with myelin basic protein (MBP), EAE was completely prevented by the administration of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. 1,25-(OH)2D3 could also prevent the progression of EAE when administered at the appearance of the first disability symptoms. Withdrawal of 1,25-(OH)2D3 resulted in a resumption of the progression of EAE. Thus, the block by 1,25-(OH)2D3 is reversible. A deficiency of vitamin D resulted in an increased susceptibility to EAE. Thus, 1,25-(OH)2D3 or its analogs are potentially important for treatment of MS
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