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Title: Modulation of intestinal dendritic cells by manipulation of enteric bacteria in intestinal inflammation
Author: Ng, Siew Chien
ISNI:       0000 0004 2682 1878
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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Inflammatory bowel disease (IBD) involves dysregulated immune responses to intestinal microbiota. Intestinal dendritic cells (DC) play a pivotal role in bacterial recognition, tolerance induction, T cell homing and differentiation. We hypothesized that alterations in human colonic DC are central to the inflammatory process, lymphocyte homing, and therapeutic responses in patients with IBD. Colonic CD11c+ cells have been shown to be activated in IBD but CD11c- cells have not been characterised. We identified, in ulcerative colitis (UC), a CD11c- population that had morphological features of DC, expressed MHC class II and Natural Killer cell marker CD56, expressed less activation markers and produced less cytokine, and were weakly stimulatory. Few were plasmacytoid DC. Their number increased in UC and Crohn’s disease (CD) but decreased after inflammation resolved. We explored function and homing properties of colonic CD11c+ DC, and their relationship with intestinal microbiota in IBD. In acute UC, IL-10+ and IL-12p40+ CD11c+ DC increased, and fewer CD11c+ DC expressed the homing molecule α-E (CD103). In active CD, IL-12p40+ DC increased and the ratio of pro:anti-inflammatory bacteria, namely bacteroides:bifidobacteria, correlated positively with IL-12p40+ DC; IL-6+ DC also increased and correlated with increased C-reactive protein, but negatively with antiinflammatory Faecalibacterium praustnitzii. In IBD probiotics and corticosteroids may work, in part, by modulating DC function. In UC patients treated with the probiotic mixture VSL#3, TLR-2+ DC and IL-12p40+ DC decreased while IL-10+ DC increased. In patients on corticosteroids similar changes were seen. Such effects were however not seen in patients on placebo. In conclusion, intestinal inflammation in IBD is associated with novel human colonic cells that share features of DC and NK cells. Intestinal DC function is influenced by composition of the commensal microbiota. Probiotics and corticosteroids are associated with altered “favourable” DC function; these effects may contribute to therapeutic benefit in patients with IBD.
Supervisor: Panoskaltsis, Nicki ; Stagg, Andrew ; Knight, Stella Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral