Modulation of Intestinal Dendritic Cells by Manipulation of Enteric Bacteria in Intestinal Inflammation
Author(s)
Ng , Siew Chien
Type
Thesis
Abstract
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.
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.
Date Issued
2009-11
Date Awarded
2009-12
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Panoskaltsis, Nicki
Stagg, Andrew
Knight, Stella
Creator
Ng , Siew Chien
Publisher Department
Division of Investigative Science
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)