An investigation of the impact of experimental colitis and inflammatory bowel disease on behaviour and on systemic and central inflammation

THESIS 10212Inflammatory bowel diseases (IBD) are chronic conditions characterised by uncontrolled inflanmiation of the intestinal mucosa. Clinical symptoms include weight loss, diarrhoea, rectal bleeding and abdominal pain. In addition to physical symptoms, patients with IBD are at increased risk of depression and anxiety. Whether these psychological disturbances occur due to stress associated with the unpleasant symptoms of IBD, or as a result of biological mediators of inflammation is unknown. It has been suggested that pro-inflammatory cytokines themselves can induce mood changes, or that cytokines (particularly interferon ? (IFN?)) can induce depression and anxiety by degrading tryptophan to kynurenine via induction of indolaniine 2,3 dioxygenase (IDO). In addition, tryptophan can be metabolised to kynurenine via tryptophan 2,3 dioxygenase (TDO). The main aim of this thesis was to investigate the association between colonic inflammation or IBD symptoms and mood/anxiety disturbances in patients, and to examine the implications of colonic inflanunation on central markers of immune activation in animal models of colitis. 18 IBD patients and 19 patient controls were scored using the Hamilton-depression (HAM-D), HAM-anxiety (HAM-A), profile of mood states (POMS), and disease activity scores (Inflammatory bowel disease questionnaire, Mayo index, and Crohn?s disease activity index). Intestinal biopsies were analysed by PCR for interleukin-6 (IL-6), IL-1?, tumor necrosis factor TNF?, inducible nitric oxide synthase (iNOS), IFN?, IDO, and matrix metalloproteases 9 (MMP9). Whole blood PAXgene analysis of IFN?, IDO, MMP9, and iNOS was examined by PCR. Circulating concentrations of IL-6, IFN?, and C-reactive protein (CRP) w\u27ere analysed by ELISA, and kynurenine and tryptophan concentrations were examined by High performance liquid chromatography (HPLC). A significant increase in HAM-D scores was found, which was independent of the psychological impact of acute symptoms, but was associated with increased colonic and circulating cytokine expression and kynurenine:tryptophan ratio

An oral alpha-galactosylceramide adjuvanted Helicobacter pylori vaccine induces protective IL-1R- and IL-17R-dependent Th1 responses

Helicobacter pylori causes chronic gastric infection that can lead to peptic ulcers and is an identified risk factor for gastric cancer development. Although much effort has been put into the development of a Helicobacter pylori vaccine over the last three decades, none has yet reached clinical application. Specific challenges pertaining to effective H. pylori vaccine development include the lack of proven vaccine-effective antigens and safe mucosal adjuvants to enhance local immune responses as well as the lack of accepted correlates of protection. Herein, we demonstrate that prophylactic intragastric immunisation with a whole-cell killed H. pylori antigen administered together with the non-toxic oral adjuvant ?-galactosylceramide (?-GalCer) induced effective immune protection against H. pylori infection in mice, which was of similar magnitude as when using the ?gold standard? cholera toxin as adjuvant. We further describe that this ?-GalCer-adjuvanted vaccine formulation elicited strong intestinal and systemic Th1 responses as well as significant antigen-specific mucosal and systemic antibody responses. Finally, we report that the protective intestinal Th1 responses induced by ?-GalCer are dependent on CD1d, IL-1R as well as IL-17R signalling. In summary, our results show that ?-GalCer is a promising adjuvant for inclusion in an oral vaccine against H. pylori infection