A251 Gut-Specific Downregulation of Interferon-Lambda Responses Occurs in Inflammatory Bowel Diseases

Abstract Background Inflammatory bowel diseases (IBD) affect 1:140 Canadians, resulting in significant inflammation and gut damage. Unlike type I and II interferons (IFNs), the most recently discovered IFNs, interferon-lambdas (IFN-λs), uniquely downregulate gut inflammation and promote gut healing in mouse models. However, it remains unknown if the important anti-inflammatory IFN-λ signaling pathways induced downstream of the IFN-λR1/IL-10RB heterodimeric receptor are altered in IBD. Aims To compare intestinal and peripheral IFN-λR levels and responses in people with active or remission IBD and those without IBD. We hypothesized that intestinal IFN-λR1 levels and downstream activities are decreased in people living with IBD, which could contribute to IBD pathology (gut inflammation and mucosal damage). Methods During routine colonoscopy, uninflamed biopsy samples were obtained from the terminal ileum and sigmoid colon. IFN-λR1 levels were quantified in intestinal biopsy and blood samples from persons with or without IBD (n=12 adults and n=12 pediatric) by immunohistochemistry and flow cytometry. Fresh intestinal biopsies were also cultured ex vivo for 24 hr in media +/- IFN-λ3 and gene expression was quantified by RT-qPCR. Results In IBD gut tissues, a significant decrease in IFN-λR1+ cells was more prominent in IBD patients with active disease (pampersand:003C0.01, 30-50% reduction). The decrease was more prominent in IBD patients with active disease. Consequently, there was a significantly lower IFN-λ-driven upregulation of genes such as IFIT1 and MX1 in IBD as compared to non-IBD tissues (pampersand:003C0.05, 4-7-fold reduction). Interestingly, IFN-λR1 levels were not decreased in peripheral blood immune cells, indicating the dysregulation of IFN-λR responses is likely gut-specific. Conclusions Our findings demonstrate that people living with IBD have dysregulated IFN-λ responses in the gut which could lead to the lower induction of key anti-inflammatory pathways. This work supports the further study of mechanisms regulating the IFN-λ system to develop strategies to restore and promote IFN-λ responses as a novel potential future IBD therapy. Funding Agencies University of Manitoba, Weston Family Foundation, The Children's Hospital Research Institute of Manitoba.