Grant: Operating Grant

Crohn's disease (CD) is a chronic inflammatory intestinal disorder with no known cure. CD patients experience symptoms such as abdominal pain, cramping, weight loss, fever, fatigue, nausea/vomiting and diarrhea. Its incidence is rising, especially in Canada, where its prevalence is said to be among the highest in the world. The painful inflammation and tissue injury characteristic of CD can be found anywhere along the digestive tract, and is thought to result from an inappropriate, exaggerated immune response in genetically-prone individuals. The currently available therapies for CD are often associated with serious side effects and highlight the need for continued research in this field. Dendritic cells (DCs) are a specialized cell type implicated in the initiation of immune responses. These cells are primarily located within tissues that are in contact with the external environment, such as the gut, where they participate in discriminating between harmful and harmless threats. Therefore, when dysregulated, DCs may misinterpret a harmless encounter as being harmful and initiate an unnecessary immune response, leading to chronic intestinal inflammation. We recently identified a subset of DCs (SIRP-alpha+ DCs) which promote intestinal inflammation in a murine model of CD. We also identified a human peripheral blood subset of DCs (SLan+) that express SIRP-alpha. In this proposal, we first aim to assess the similarity of murine SIRP-alpha+ and human SIRP-alpha+SLan+ DCs. Next, we intend to fully characterize SIRP-alpha+SLan+ DCs in human tissues and compare them in CD patients and controls. Finally, we will evaluate the therapeutic potential of inhibiting SIRPalpha+ DC trafficking in a murine model of intestinal inflammation. As such, the identification of the human counterpart of murine SIRPalpha+ DCs may contribute to our knowledge of disease pathogenesis and/or translate into the development of new therapeutic targets.