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Project
The role of regulatory T-cells and IL-13 in the treatment of chronic inflammatory bowel diseases and intestinal fibrosis.
Crohns disease is in essence a transmural disease in which chronic intestinal inflammation leads to perforating ulcers (due to insufficient mucosal healing) and intestinal wall fibrosis (due to excessive healing). Despite the clinical importance of fibrosis in IBD, until now, there is no clue about the time course, the pathophysiology or the treatment, norare there good markers of fibrosis in serum, imaging tools or good animal models to study fibrosis. Therefore, the general aim of this study was to develop a chronic model of relapsing murine colitis mimicking humandisease in order to acquire in depth knowledge on the mechanisms responsible for intestinal fibrosis. Next, we aimed to search for non-invasiveimaging tools to assess intestinal inflammation and fibrosis.
We have set up a reliable chronic colitis model in mice by exposing themto repeated cycles of administration of DSS followed by a recovery period. In this chronic model of inflammatory colitis which pathologically mimics human CD, we showed that the adaptive immune system is activated with induction of Th1 and Th17 cells in MLNs. This effect is progressive with an increasing number of cycles of administration of DSS. Inhibitionof T cell associated cytokines IFN-γ and IL-17F during the chronicphase of inflammation did not alter the deposition of collagen. Anti-IL-17A slightly promoted fibrosis. Next, we showed that fibrosis can be induced by chronic DSS colitis in RAG-1 deficient mice on the C57BL/6 background, suggesting that the adaptive immune system is not crucial for fibrogenesis in chronic DSS colitis. Furthermore, transcriptomic analysis of colonic gene expression in the different phases of inflammation and fibrosis, provided information on the differential regulation of genes during inflammation, fibrosis and recovery. During prolonged recovery after the induction of fibrosis, an upregulation of keratins was observed. Atype I IFN-related gene signature could be identified in chronic colitis in RAG-1 KO mice as compared to WT mice. Finally, we showed that in vivo T2 relaxometry is a promising non-invasive assessment tool of inflammation and fibrosis of the bowel wall in murine colitis. Furthermore, in a clinical setting, MRI T2 relaxometry of the pelvis was feasible in patients with IBD and a histogram shift compared to healthy volunteers reminiscent of chronic DSS colitis was observed.
We have set up a reliable chronic colitis model in mice by exposing themto repeated cycles of administration of DSS followed by a recovery period. In this chronic model of inflammatory colitis which pathologically mimics human CD, we showed that the adaptive immune system is activated with induction of Th1 and Th17 cells in MLNs. This effect is progressive with an increasing number of cycles of administration of DSS. Inhibitionof T cell associated cytokines IFN-γ and IL-17F during the chronicphase of inflammation did not alter the deposition of collagen. Anti-IL-17A slightly promoted fibrosis. Next, we showed that fibrosis can be induced by chronic DSS colitis in RAG-1 deficient mice on the C57BL/6 background, suggesting that the adaptive immune system is not crucial for fibrogenesis in chronic DSS colitis. Furthermore, transcriptomic analysis of colonic gene expression in the different phases of inflammation and fibrosis, provided information on the differential regulation of genes during inflammation, fibrosis and recovery. During prolonged recovery after the induction of fibrosis, an upregulation of keratins was observed. Atype I IFN-related gene signature could be identified in chronic colitis in RAG-1 KO mice as compared to WT mice. Finally, we showed that in vivo T2 relaxometry is a promising non-invasive assessment tool of inflammation and fibrosis of the bowel wall in murine colitis. Furthermore, in a clinical setting, MRI T2 relaxometry of the pelvis was feasible in patients with IBD and a histogram shift compared to healthy volunteers reminiscent of chronic DSS colitis was observed.
Date:1 Oct 2009 → 15 Apr 2014
Keywords:Intestinal fibrosis, Chronic inflammatory bowel disease
Disciplines:Endocrinology and metabolic diseases, Gastro-enterology and hepatology, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences
Project type:PhD project