The objective of this project is to define the cellular and molecular targets of vitamin D as a regulator of inflammatory bowel disease (IBD). IBD are immune mediated diseases of unknown etiology affecting the gastrointestinal tract. Higher incidences of IBD occur in the northern climates of the United States and Europe; places where sunshine and vitamin D synthesis in the skin are low. Experimentally; vitamin D deficiency exacerbated symptoms of IBD in mice, which spontaneously develop enterocolitis {interleukin (IL) 10 knockout (KO)}. Supplementation with hormonally active vitamin D (1,25(OH)2D3) for as little as 2 weeks ameliorated IBD symptoms in these mice. IL10 KO mice, which cannot respond to vitamin D (vitamin D receptor; VDR/IL10 double KO) develop a fulminating form of IBD, which was transferred to T and B cell deficient mice by both CD4+ or CD8+ T cell injections. A second experimental model of IBD (CD45RBhigh induced) was more severe when the T cells were VDR KO compared to wildtype. The proposal described here will test the hypothesis that vitamin D is a physiological regulator of the CD4+ and CD8+ T cells, which cause and/or suppress IBD disease. IBD inducing T cells will be isolated and treated in vitro and in vivo with and without vitamin D and the functions of the T cells will be compared for the ability of the cells to induce disease in naive mice. The use of VDR KO mice will be included to determine whether there is a physiological role for vitamin D in the development/regulation of T cells, which induce or suppress IBD. The experiments described here are designed 1) to determine the mechanisms underlying 1,25(OH)2D3 mediated suppression of experimental IBD; 2) to determine whether IBD develops in germfree VDR/IL10 double KO mice 3) to determine which T cell functions and genes are targets of vitamin D in CD4+ T cells 4) to determine which T cell functions and genes are targets of vitamin D in CD8+ T cells and 5) to determine whether CD4+ and/or CD8+ T cells from VDR KO mice can transfer or suppress IBD. A better understanding of the mechanisms underlying vitamin D regulation of T cells and IBD may lead to improved therapies for patients with IBD. ? ? ?

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG1-HAI-K (09))
Program Officer
Hamilton, Frank A
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Pennsylvania State University
Schools of Allied Health Profes
University Park
United States
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Waddell, Amanda; Zhao, Jun; Cantorna, Margherita T (2015) NKT cells can help mediate the protective effects of 1,25-dihydroxyvitamin D3 in experimental autoimmune encephalomyelitis in mice. Int Immunol 27:237-44
Chen, Jing; Bruce, Danny; Cantorna, Margherita T (2014) Vitamin D receptor expression controls proliferation of naïve CD8+ T cells and development of CD8 mediated gastrointestinal inflammation. BMC Immunol 15:6
Ooi, Jot Hui; Chen, Jing; Cantorna, Margherita T (2012) Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol Aspects Med 33:77-82
Yu, Sanhong; Cantorna, Margherita T (2011) Epigenetic reduction in invariant NKT cells following in utero vitamin D deficiency in mice. J Immunol 186:1384-90
Cantorna, Margherita T (2011) Why do T cells express the vitamin D receptor? Ann N Y Acad Sci 1217:77-82
Bruce, Danny; Cantorna, Margherita T (2011) Intrinsic requirement for the vitamin D receptor in the development of CD8??-expressing T cells. J Immunol 186:2819-25
Bruce, Danny; Yu, Sanhong; Ooi, Jot Hui et al. (2011) Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling. Int Immunol 23:519-28
Bruce, Danny; Ooi, Jot Hui; Yu, Sanhong et al. (2010) Vitamin D and host resistance to infection? Putting the cart in front of the horse. Exp Biol Med (Maywood) 235:921-7
Sanderson, Peter; Elsom, Rachel L; Kirkpatrick, Verity et al. (2010) UK food standards agency workshop report: diet and immune function. Br J Nutr 103:1684-7
Cantorna, Margherita T (2010) Mechanisms underlying the effect of vitamin D on the immune system. Proc Nutr Soc 69:286-9

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