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Title: The immunomodulatory effects of vitamin D in Crohn's disease : dendritic cells, gamma delta T-cells and homing
Author: Milestone, Andrew Neill
ISNI:       0000 0004 2728 447X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Background: Emerging epidemiological evidence implicates Vitamin D insufficiency in the risk of Inflammatory Bowel Disease (IBD). Dendritic cells (DC) are thought to play a pivotal role in the dysregulated intestinal mucosal T-cell mediated immune responses which characterise IBD. In vitro human blood studies and in vivo animal models of IBD, suggest that vitamin D is immunomodulatory inducing a tolerogenic DC phenotype and influencing leucocyte homing properties with potential therapeutic applications. Aims: 1) Determine Vitamin D status in Crohn’s Disease (CD) patients and identify associations with patient and disease phenotype; 2) Determine homing molecule expression by circulating DC and T-cells, and the phenotypic properties of gamma-delta (γδ) T-cell populations in IBD patients and healthy controls; 3) Determine in vitro immunomodulatory effects of 1,25-dihydroxyvitamin D3 (1,25-OH2D3) on co-stimulatory and functional phenotype of monocyte-derived DC and low density cells (LDC) enriched for DC isolated from peripheral blood and the terminal ileum. Results: Vitamin D insufficiency was common in CD. Serum 25-hydroxyvitamin D negatively correlated with the Harvey Bradshaw Index and Physicians’ Rating of Disease Activity, but was not associated with disease phenotype including distribution and use of immunosuppression. There were no significant differences in the expression of gut and skin homing markers on circulating DC or T-cells in patients with CD compared with healthy controls. The circulating γδ T-cell population was reduced in active IBD compared with controls. Aberrant expression of skin-homing molecules on γδ T-cells, conventional T-cells and DC was demonstrated in a CD patient with an extra-intestinal cutaneous manifestation of IBD, abrogated upon clinical resolution in response to treatment with corticosteroids. 1,25OH2D3 promoted a functionally immature tolerogenic phenotype and monocyte-like state in LDC and monocyte-derived DC in vitro. Initial investigations suggest that vitamin D impairs the ability of DC from the terminal ileum to stimulate T-cell proliferation. Conclusion: Vitamin D insufficiency is common in IBD. Vitamin D status correlated with clinical disease activity in Crohn’s Disease. Vitamin D exerts immunomodulatory effects in vitro on MoDC and LDC, supporting the potential application of Vitamin D for therapeutic use in IBD.
Supervisor: Knight, Stella ; Omar, Hafid ; Hart, Ailsa ; Walters, Julian Sponsor: St. Mark's Hospital for Diseases of the Rectum and Colon (London, England) ; Procter & Gamble Company
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral