Mo1738 Efficacy of a Novel JAK1-Specific Inhibitor in a Mouse Model of Acute and Chronic Colitis

Abstract

Introduction and aim: Indoleamine 2,3-dioxygenase (IDO) is expressed in innate immune cells and acts as the first rate-limiting step in the tryptophan (TRP) catabolism along the kynurenine pathway. Decreased serum TRP levels have been associated with active inflammation in Crohn's disease (CD) due to induction of IDO (Gupta, Inflamm Bowel Dis 2012). We studied the effect of infliximab-induced downregulation of inflammation on serum levels of TRP and kynurenine, as well as mucosal IDO expression in patients with inflammatory bowel disease (IBD). Methods: Serum samples and endoscopically-derived ileal or colonic mucosal biopsies were obtained from controls and patients with active IBD, and this before and after their first treatment with infliximab. Short-term clinical response and mucosal healing were assessed by experienced clinicians at 4 or 10 weeks after a single infusion or induction schedule, respectively (Ferrante, Inflamm Bowel Dis 2007; Schnitzler, GUT 2009). Serum TRP and kynurenine were measured by high performance liquid chromatography, and IDO mucosal gene expression was measured by Affymetrix Human Genome U133 Plus 2.0 Arrays. Data were analyzed with SPSS software using non-parametric tests and p-values of 9-fold increased in active IBD patients before infliximab therapy vs. controls (pileum=0.001 and pcolon<0.001). Although the IDOmucosal expression levels significantly decreased after infliximab therapy in IBD responders when compared to their baseline samples (pshort-term response and pmucosal healing<0.001), the colonic expression still remained significantly higher than controls (pshort-term response<0.001 and pmucosal healing=0.002). Serum TRP levels were significantly decreased (p<0.001) and the kynurenine/ tryptophan (K/T) ratio was significantly increased (p=0.001) in active IBD patients when compared to controls. However, we found no significant effect of infliximab therapy on both the TRP levels and K/T ratio. Conclusion: This study demonstrates that mucosal IDO expression levels are increased and serum TRP levels decreased in IBD patients with active disease. Of note, after controlling the inflammation with infliximab therapy, both levels remained impaired in IBD responders showing a complete mucosal healing. This persistent upregulation of IDO in patients with complete colonic healing may explain why mucosal ulcers recur very early if patients do not receive maintenance therapy with infliximab.