Helicobacter-induced CD4+ Th17 responses in intestinal inflammation

Inflammatory bowel disease (IBD), including Crohn?s disease and ulcerative colitis, is a significant health concern worldwide. In the United Kingdom alone there are ~150,000 people affected and 9,000 new cases diagnosed each year. With no cure existing, available treatments (medications, nutritional therapies, and surgery) are aimed at dampening the inflammation in the gut, thereby reducing the symptoms for the individual. However, there are many patients for whom these therapies are not effective, making the development of new therapeutic treatments a main priority and necessity.

The cause of IBD is not known; however, the intestinal bacterial flora is believed to be one factor contributing to the onset of disease in patients with these illnesses. A group of white blood cells called T helper (Th) lymphocytes that are part of the body?s immune system are believed, for unknown reasons, to ?attack? bacteria in the gut leading to intestinal inflammation. Recent data from both experimental models and human genetic studies has revealed that a protein called interleukin-23 (IL-23) plays an important role in the development of intestinal inflammation. It is currently unclear how IL-23 contributes to chronic inflammation; however, evidence suggests that this protein is essential for the expansion of a particular type of Th lymphocytes called Th17 cells. Th17 cells are believed to contribute to tissue pathology in certain autoimmune diseases through their production of the cytokines IL-17 and IL-22. To date, very little is known about the role of Th17 cells in intestinal inflammation. Thus, further research in this area will help our understanding of the process by which bacteria induce pathology in the gut, information that will be of utmost importance for the design of new therapeutic intervention strategies for IBD.

In this project, we will use an experimental model of intestinal inflammation involving infection with the bacterium Helicobacter hepaticus to study Th17 cells in intestinal pathology. In particular, we will examine how these cells develop and survive in the gut, and also characterize their production of cytokines such as IL-17 and IL-22 at different time points following infection. Moreover, we will use various novel in vivo approaches to block the action of Th17 cells or the cytokines they secrete to elucidate their role in the inflammatory process. Together, our studies will provide important information concerning harmful immune responses to intestinal bacteria that will help in the design of strategies towards the treatment of IBD in humans.

Inflammatory bowel disease (IBD), including Crohn?s disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract that is caused in part by a dysregulated immune response to the intestinal bacterial flora. Using experimental models and human genetic studies, recent evidence from our group and others has demonstrated an important role for IL-23 and IL-23R signaling in the development of colitis. Although the precise mechanism by which IL-23 contributes to intestinal inflammation is unknown, reports over the past year have demonstrated that this cytokine is involved in the expansion of a novel CD4+ T cell subset termed Th17. These CD4+ T lymphocytes are characterized by their production of IL-17A, IL-17F, and IL-22, and have been implicated in disease pathogenesis in experimental autoimmune encephalomyelitis, another inflammatory disorder that is dependent on IL-23. Data from our Helicobacter hepaticus colitis model demonstrate increased production of T cell-derived IL-17A in mice with intestinal inflammation, opening up the possibility that the Th17 subset is involved in disease pathogenesis also in the intestinal tract. In this project, we will use our recently described model of intestinal inflammation involving anti-IL-10R treatment of H. hepaticus-infected WT mice to define the mechanisms underlying the IL-23 dependence of bacterial-induced T cell-dependent colitis. In particular, we will focus on Th17 cells and on experimental in vivo approaches where access to novel reagents will give us a competitive advantage in the field. The aims of this application are therefore:

1) To define the contribution of IL-17 versus IL-22 in H. hepaticus-induced colitis using anti-IL-17F and anti-IL-22 mAb as well as mice with a T cell specific deletion in gp130.

2) To functionally characterize the Th17 cells arising following H. hepaticus infection to establish the heterogeneity of this population in vivo.

3) To determine the kinetics of cecal versus colonic cytokine responses following H. hepaticus infection to elucidate the contribution of Th1 versus Th17 cells in intestinal inflammation at these two sites.

By characterizing H. hepaticus-induced Th17 responses and determining the role of these cells in disease pathogenesis, our studies will provide important new information concerning harmful immune responses to intestinal bacteria that will help in the design of strategies towards the treatment of chronic intestinal inflammation. Links fostered through the Hull York Medical School will ensure that results broadly applicable to chronic inflammation will be highlighted and opportunity for clinical research fully explored.