Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a significant health concern in the developed world, and the number of affected individuals is on the rise in both Europe and the USA. The cause of IBD is not known; however, the intestinal bacterial flora and an inappropriate ("pathogenic") immune response to these bacteria are believed to contribute to the onset of disease. Despite available treatments for humans with IBD (medications, nutritional therapies, and surgery) there are many patients for whom these therapies are not effective. Thus, increased knowledge of the interactions between intestinal bacteria and the immune system in individuals with and without disease is of utmost importance as such information m ay aid in the development of new therapies for IBD.
This project aims to identify the mechanisms by which bacteria trigger intestinal inflammation in disease-susceptible individuals. Using an experimental model of IBD involving infection with Helicobacter hepaticus, we will focus on the initial encounter between bacteria and cells of the innate immune system and examine how these interactions lead to the development of a pathogenic T cell response and subsequently disease. The two specific objectives of this proposal are to explore the mechanism by which H. hepaticus activates cells of the innate immune system, and to identify the anatomical location where priming of disease-inducing T cells occurs. These objectives will be achieved using cellular immunology methods and a newly developed transgenic mouse model incorporating the T cell receptor of a disease-inducing T cell clone directed against a defined protein of H. hepaticus.
The proposed project is likely to provide new insights into the mechanisms underlying the induction and regulation of intestinal inflammation, and support from the European Commission will actively help establish the applicant's research program in the EU.
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