O037 Differential roles for IL-23 and IL-17 in inflammatory bowel disease

Introduction Th17 cells and their signature cytokine IL-17A have been implicated in a number of autoimmune diseases including inflammatory bowel disease (IBD). IL-23 is a closely related cytokine to IL-12 in that it shares both a ligand and a receptor subunit. IL-23 drives expression of IL-17A and IL-17F in a number of cell types including Th17 cells. IL-23, IL-17A and IL-17F expression are elevated in IBD and SNPs in the IL-23R show strong association with Crohn’s disease and ulcerative colitis. Methods To examine the role of these cytokines in the gut, we compared inhibition of IL-23p19 and IL-17RA in the Helicobacter bilis-infected mdr1a−/− mouse model of colitis. Results Inhibition of IL-23 alone provided strong efficacy comparable to that seen with an IL-12/23p40 dual inhibitor. Surprisingly, IL-17RA antagonism did not protect mice from disease, and in fact led to acute disease exacerbation. IL-17RA is a necessary receptor for multiple IL-17 family cytokines including IL-17A, IL-17F and IL-25. To better understand which IL-17 family cytokines drive inflammation through IL-17RA in the gut, we compared inhibition of IL-17RA with inhibition of IL-17A, IL-17F or IL-25. IL-17A inhibition resulted in disease exacerbation similar to that seen with inhibition of IL-17RA, while inhibition of the other IL-17 family cytokines had no effect. Subsequent studies found that IL-17RA inhibition did not exacerbate disease in uninfected mdr1a−/− mice. The dependence on the presence of H. bilis for the exacerbation suggests either a role for IL-17A in maintenance of barrier integrity or in control of pathogens in the gut. In order to further investigate the mechanisms underlying disease exacerbation in anti-IL-17RA treated H. bilis-infected mdr1a−/− mice, we examined gene expression changes in the gut. IL-23 inhibition led to decreased expression of a number of cytokines and chemokines in the gut while IL-17RA or IL-17A inhibition led to increased expression of many genes including IFNγ, TNFα, IL-6 and a number of chemokines. To determine whether an increase in IFNγ was key to the anti-IL-17RA mediated exacerbation, we treated mice with anti-IFNγ along with anti-IL-17RA. Inhibition of IFNγ alone was highly efficacious; however, IFNγ blockade did not affect disease in the presence of anti-IL-17RA. These data suggest that pathways other than IFNγ may be driving anti-IL-17RA mediated disease exacerbation in this mouse model of colitis and the exacerbation is not likely due to a shift from Th17 cells to Th1 cells. Conclusion The data in this H. bilis-infected mdr1a−/− mouse colitis model are similar to what is emerging from Crohn’s disease clinical trials: IL-12/23p40 inhibitors are showing promise while inhibition of IL-17A with secukinumab led to exacerbation in a subset of patients. The secukinumab data in Crohn’s disease patients are in contrast to the data in psoriasis patients where inhibition of IL-17A, IL-17RA or IL-23 have shown promising efficacy. Together the emerging clinical data suggest that the role of Th17 cells and IL-17A in colitis is different from other inflammatory diseases and that IL-23 and IL-17 biology are distinct in the gut.