Grant: Project Grant

Chronic intestinal inflammatory diseases are highly prevalent in Canada. They are characterized by tissue injury driven by the aberrant production of molecules called inflammatory cytokines, which are often induced when immune cells of the intestinal tissue are exposed to microbes. Some of these cytokines are targeted by immunotherapies with antibodies that neutralize their function. However, they have limited efficacy thus it is necessary to develop improved treatment options. Interleukin-15 (IL-15) is a pro-inflammatory cytokine that in normal conditions promotes the growth and maintenance of important cells of the immune system and is critical for the resolution of infections. However, IL-15 is also found associated with a number of pathological conditions (diabetes, arthritis and psoriasis) in which it is suspected of a deleterious contribution. IL-15 is one of the pro-inflammatory cytokines with increased production in intestinal inflammation but it is not fully clear yet how much and how it may contribute to these diseases. Our preliminary results in a mouse model of experimentally induced intestinal inflammation show that IL-15 signaling by unknown mechanisms contributes to pathological inflammation of the gut and suggest that targeting IL-15 could be a promising therapeutic approach for the treatment of chronic intestinal inflammation. In this project, we will use genetically deficient mice and advanced biochemical and cell biology techniques to elucidate the mechanisms by which IL-15 contributes to pathological inflammation in the gut. We will also therapeutically inhibit IL-15 activity to evaluate the efficacy of IL-15 neutralization in reducing the severity of inflammation. We will extend these studies to human tissues and intestinal organ cultures to determine the feasibility of inhibiting IL-15 in human cells. The results from this study can help in the design of better drugs that will efficiently target IL-15 in intestinal inflammatory diseases.