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. ? ? ?
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