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Title: The modulation of human dendritic cells by glucagon like peptide-2
Author: Tee, Cheng Tai
ISNI:       0000 0004 5367 4869
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Glucagon-like peptide-2 (GLP-2) is a pleiotropic peptide secreted in the human intestine with known intestinotrophic properties beneficial in conditions like short bowel syndrome (SBS); a condition characterized by malabsorption of both fluid and nutrients. Left untreated, SBS can lead to dehydration, malnutrition, and weight loss. Teduglutide, a long acting analogue of GLP-2, has been used in multiple clinical studies to elucidate its trophic properties. Murine studies however have also shown that GLP-2 inhibits pro-inflammatory cytokines raising the possibility of an anti-inflammatory property and its potential use in intestinal inflammatory conditions; in particular inflammatory bowel disease (IBD). Dendritic cells (DC) play a central role in the initiation and regulation of the immune system. They bridge the innate and adaptive immune systems and are unique in their ability to activate naïve T cells as well as dictate the type of T-cell immunity. We hypothesized that GLP-2 has an immunomodulatory role and exert this action via DC. Toxic effects of GLP-2 peptide on human DC in-vitro have not previously been experimented. Our experiments showed that GLP-2 did not have a toxic effect on DC at 1pM, 1nM and 1μM concentrations and hence we were subsequently able to look at the effects of GLP-2 on human DC phenotype and function. Using whole blood and intestinal biopsies from healthy volunteers, we obtained a population of enriched low density cells (LDC) which offered a novel and 'physiological' model for DC. These cells were labelled with appropriate fluorochromes and assayed by a flow cytometer. We established that DC incubated overnight with GLP-2 had a reduced intensity ratio of HLA DR and an increased expression of CD14 in a dose dependent way compared with controls. The expression of co-stimulatory molecule CD86 was also higher in the treated DC. This phenotypic change suggests that GLP-2 modulated DC into an immature state although still able to stimulate T-cell proliferation. Ongoing cytokine production of IFN-γ and IL-12 from healthy blood DC was inhibited by GLP-2 however only cytokine production of IFN-γ from intestinal lamina propria DC was inhibited. These findings suggest that GLP-2 may induce a 'homeostatic' or 'immuno-tolerant' state and block Th1 cytokines in DC. Functional experiments confirmed that GLP-2 modulated DC enhanced T cell proliferation although this occurred only with intestinal DC. GLP-2 conditioned DC also functionally affected the cytokine profile of T cells by reducing the cytokines IFN-γ in both human blood and intestinal DC and IL-12 in only the latter. Hence our human DC in-vitro findings mirror some of the results found in murine studies showing GLP-2 effects on blocking Th1 cytokines. The results suggest that GLP-2 has an immunoregulatory effect and that the mechanism of action may possibly involve direct effects on DC. GLP-2 therefore is able to modulate DC characteristics and function leading to future application as an immunotherapy for inflammatory diseases.
Supervisor: Gabe, Simon ; Knight, Stella ; Omar, Hafid Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral