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Identification of the mechanisms by which Helicobacter induces intestinal inflammation

Final Activity Report Summary - BACTERIA IBD (Identification of the mechanisms by which Helicobacter induces intestinal inflammation)

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic inflammatory disorder of the intestinal tract. The disease is a significant health concern in the developed world and the number of affected individuals is on the rise in both Europe and North America. The cause of IBD is not known; however, the intestinal bacterial flora and an inappropriate immune response to these bacteria are believed to contribute to the disease onset. Despite available human treatments with IBD, such as 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 is of utmost importance, as such information may aid in the development of new therapies for IBD.

In this project, we used an experimental model of intestinal inflammation involving infection with the bacterium helicobacter hepaticus. The objectives of the project were to:

1. explore the interactions between h. hepaticus and cells of the immune system, in particular a cell type called the dendritic cell, and
2. identify where in the body a type of white blood cell called the T lymphocyte first met the bacterium.

The dendritic cell is one of the first cells of the immune system that encounters bacteria in the intestinal tract and plays an important role in guiding the immune system to respond properly to these microbes. The dendritic cell does this by ‘engulfing’ bacteria and presenting small bacterial pieces to another cell type of the immune system called the T lymphocyte. To investigate how the dendritic cell recognised bacteria, we established a method in the lab to generate large numbers of these cells in vitro. We subsequently cultured the dendritic cells in the presence of h. hepaticus and found that they responded to and became activated after seeing the bacterium. Thus, the dendritic cells secreted molecules known as ‘cytokines’ that were shown to be important for the immune response and they also changed their cell surface structure and increased the expression of various molecules which were important for the interaction with T lymphocytes. We further identified a specific cell surface molecule on the dendritic cell that was responsible for recognising the bacterium. This molecule belonged to the Toll-like receptor family, a group of proteins that was previously shown to recognise various microbial products.

To examine where in the body T lymphocytes first encountered intestinal bacteria, we initially had to develop various reagents and methods and optimise our experimental system. For example, the project involved experiments in which T lymphocytes were labelled with a green dye to be able to follow their movement and location in vivo. We also developed a method by which we could now look at T lymphocytes isolated from the intestinal tract to examine their production of the above-mentioned group of molecules called cytokines. Our findings so far demonstrated that T lymphocytes saw pieces of h. hepaticus presented by dendritic cells in lymph nodes draining the intestinal tract. Ongoing experiments were now aimed at identifying additional locations in the body where T lymphocytes might encounter the bacterium.

Taken together, as a result of the work carried out with the support from the European Community, we were now starting to understand more about how the host immune system sensed and responded to bacteria from the intestinal tract, both at the levels of the dendritic cell and the T lymphocyte. Our hope was that this research would provide important information that would down the line help in the design of strategies towards the treatment of humans with IBD.