There are profound effects of vitamin D on immune function. There is data to suggest that increased levels of vitamin D (either through diet, supplements or sunlight exposure) are beneficial for multiple sclerosis (MS) patients. In addition, active vitamin D (1,25(OH)2D3) treatment of experimental autoimmune encephalomyelitis (EAE) blocks the development of disease. In the first year of life infants undergo considerable fluctuation in their circulating vitamin D (25(OH)D3) levels. We hypothesize that early changes in vitamin D have profound effects on the thymus such that iNKT cells fail to develop and as a result autoimmune diseases like MS are more likely to develop. iNKT cells require adequate vitamin D in utero and the expression of the vitamin D receptor (VDR) for both development and function. iNKT cells have been implicated as inhibitors and regulatory cells in EAE and MS. The hypothesis to be tested is that vitamin D regulates iNKT cells and as a result is important for shaping the developing immune response and preventing and controlling the development of autoimmunity. The goals of this proposal are to determine the molecular mechanisms underlying vitamin D and the VDRs effects on iNKT cells.
The aims are to determine the plasticity of the iNKT cell response as a function of changes in vitamin D status, determine the role of vitamin D in the thymus for iNKT cell development, determine how changes in vitamin D affect proliferation, survival and death of iNKT cells, and to determine the role of active vitamin D (1,25(OH)2D3) regulation of iNKT cells in suppression of EAE and whether changes in vitamin D status in vivo or 1,25(OH) 2D3 in vitro regulates human NKT cell expansion and function. NKT cells are novel targets in MS and a better understanding of the mechanisms by which their development and function are regulated by vitamin D and 1,25(OH)2D3 would be critical for manipulating NKT cells therapeutically.

Public Health Relevance

There is at present a great deal of misinformation about vitamin D and vitamin D supplements as immune system modulators in the public forum. Identifying the cellular and molecular targets of vitamin D in the immune system is important so that rational decisions about the use of vitamin D supplements and/or active vitamin D compounds to manipulate the immune system and prevent or treat autoimmune diseases like multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067563-04
Application #
8454506
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Utz, Ursula
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$299,692
Indirect Cost
$92,820
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
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Whitcomb, James P; Deagostino, Mary; Ballentine, Mark et al. (2012) The Role of Vitamin D and Vitamin D Receptor in Immunity to Leishmania major Infection. J Parasitol Res 2012:134645

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