The objective of this proposal is to define molecular and cellular targets of vitamin D in the immune system. There is a large body of anecdotal data to suggest that there is a link between vitamin D status and the human autoimmune disease multiple sclerosis. Experimentally, vitamin D deficiency exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Furthermore supplementation of mice with vitamin D can suppress and prevent symptoms of EAE. Two targets of vitamin D in the immune system have been identified the interleukin (IL)-4. secreting type-2 helper T (Th2) cells and transforming growth factor (TGF)-beta1 (two cytokines shown to be protective in EAE) secreting cells. The hypotheses to be tested are: 1. Vitamin D status regulates Th cell differentiation. 2. Vitamin D treatment of EAE results because of the induction of Th2 cells. 3. Vitamin D induction of Th2 cells and protection from EAE depends on TGF-beta1 synthesis. 4. Vitamin D negatively regulates Th1 effector cells. Th cell differentiation and function will be measured as a function of increasing vitamin D both in vitro and in vivo in Th cells from T cell receptor transgenic mice. T cells from vitamin D treated mice will be isolated and tested for their ability to transfer protection from EAE. TGF-beta1 will be neutralized in vitro and in vivo to determine if vitamin D functions via the transcriptional upregulation of TGF-beta1. Similarly, TGF-beta1 supplementation will be done and compared to vitamin D treatment for the mechanisms by which they suppress EAE. Th2 cell deficient mice will be used as a source of Th1 effector cells and vitamin D will be tested as a direct regulator of Th1 function. A better understanding of how vitamin D effectively blocks EAE is necessary for proper nutritional counseling and optimal treatment of multiple sclerosis patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038888-02
Application #
6490952
Study Section
Nutrition Study Section (NTN)
Program Officer
Nunn, Michael
Project Start
2001-01-05
Project End
2004-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
2
Fiscal Year
2002
Total Cost
$204,739
Indirect Cost
Name
Pennsylvania State University
Department
Nutrition
Type
Schools of Allied Health Profes
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
Yu, Sanhong; Cantorna, Margherita T (2008) The vitamin D receptor is required for iNKT cell development. Proc Natl Acad Sci U S A 105:5207-12
Wittke, Anja; Chang, Andrew; Froicu, Monica et al. (2007) Vitamin D receptor expression by the lung micro-environment is required for maximal induction of lung inflammation. Arch Biochem Biophys 460:306-13
Froicu, Monica; Cantorna, Margherita T (2007) Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol 8:5
August, Avery; Mueller, Cynthia; Weaver, Veronika et al. (2006) Nutrients, nuclear receptors, inflammation, immunity lipids, PPAR, and allergic asthma. J Nutr 136:695-9
Froicu, Monica; Zhu, Yan; Cantorna, Margherita T (2006) Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice. Immunology 117:310-8
Cantorna, Margherita T; Mahon, Brett D (2005) D-hormone and the immune system. J Rheumatol Suppl 76:11-20
Zhu, Yan; Mahon, Brett D; Froicu, Monica et al. (2005) Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur J Immunol 35:217-24
Cantorna, Margherita T; Zhu, Yan; Froicu, Monica et al. (2004) Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. Am J Clin Nutr 80:1717S-20S
Cantorna, Margherita T; Mahon, Brett D (2004) Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood) 229:1136-42
Froicu, Monica; Weaver, Veronika; Wynn, Thomas A et al. (2003) A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol 17:2386-92

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