Grant: Fellowship - Priority Announcement: Gastroenterology

Canada has some of the highest rates of inflammatory bowel disease (IBD) in the world. The causes of IBD are complex, but one likely factor is an imbalance in gut immune responses. Immune cells, specifically the subset of immune cells called T cells, are of particular importance. There are two types of T cells that have competing functions: effector cells, which generally cause inflammation, and regulatory cells (Tregs), which suppress inflammation. Under healthy conditions the effector cells are kept in-check by the regulatory cells. Evidence suggests that shifts in this equilibrium between regulatory and effector T cells may contribute to the pathogenesis of IBD; when there is an imbalance, inflammation flares up and damage to the gut can occur. T cells secrete a molecule called integrin a4ß7 that helps T cells migrate to the gut; therefore, a4ß7 is thought to have a role in IBD. Clinical trials of a commercial antibody called Vedolizumab (which binds to a4ß7, rendering it dysfunctional) have shown a reduction in IBD symptoms after treatment. It is not known how Vedolizumab works, but it is likely related to control of inflammatory effector T cells and the function of regulatory T cells in the intestine. Both effector and regulatory T cells express a4ß7, but how Vedolizumab affects their homing in the gut is unknown. The primary goal of my proposal is to study how Vedolizumab affects the homing and function of effector versus regulatory CD4+ T cells in the gut of IBD patients. In addition, I will determine if human Tregs that express a4ß7 can cure IBD in a mouse model. Understanding the mechanism of action of Vedolizumab is key to understanding more about the pathogenesis of IBD and optimizing the use of this therapy to treat IBD patients. This project will also determine if the use of a4ß7+ Tregs to treat IBD patients is a suitable option to reduce the symptoms of IBD.