Grant: CIHR Fellowship

Inflammatory bowel disease (IBD) is a group of severe, incurable chronic conditions which affect approximately 1/150 Canadians. IBD results from uncontrolled inflammation in the gut, causing symptoms such as diarrhoea, abdominal pain, bleeding and weight loss. IBD is driven by an imbalance of various types of immune cells which are normally present in specific proportions. I am interested in two cell types: effector T cells (Teff) which help fight infections, and regulatory T cells (Treg) which control Teffs and prevent healthy cells from being accidently attacked. In IBD, too few Tregs are present in the gut thus uncontrolled Teffs end up attacking intestinal tissues. Studies in humans have demonstrated that injecting large numbers of Tregs can help restore the balance of Teffs and Tregs in the gut and inhibit IBD. However, obtaining enough cells to accomplish this is difficult. In this project, I will investigate whether Tregs can be made more potent such that the number of Tregs required to treat IBD is reduced. Research has shown that Tregs which specifically recognise intestinal molecules are better at inhibiting IBD. This is partially because intestine-specific Tregs stay in the gut instead of circulating throughout the body. A molecule often found in the gut which is expressed by E.coli and commonly attacked in IBD patients is "flagellin". In this project, I aim to increase the therapeutic potency of Tregs by genetically modifying them to recognise flagellin. I will investigate whether flagellin-specific Tregs suppress IBD development/progression more effectively than unmodified Tregs in three models of IBD, including a humanised mouse model. I will then re-engineer this approach to be suitable for clinical use. Overall, I expect my findings to critically inform the future clinical investigation of flagellin-specific Tregs for treating IBD. This work can potentially transform how IBD is treated, offering a highly desirable cure with minimal side-effects.