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P138. Infliximab modulates IL23–IL17 axis in patients with inflammatory bowel diseases

F. Caprioli1, F. Bosè2, C. Viganò1, M. Palazzo1, S. Ferrero1, D. Conte1, S. Abrignani2, E. Reali2

1University of Milan, Milan, Italy; 2Istituto Nazionale di Genetica Molecolare, Milan, Italy

Aim: Antibodies against tumor necrosis factor alpha (TNF-α) represent an effective therapy for patients with inflammatory bowel diseases (IBD), even if their mechanism of action is not fully understood. In patients with psoriasis, TNF-α neutralization leads to a reduced dermal infiltration by mature dendritic cells and macrophages, and to a reduced expression of Th17-related cytokines. This study was aimed to evaluate the effects of infliximab on intestinal cytokine expression in patients with active IBD, and to correlate the variations with endoscopic response to therapy.

Material and Methods: 16 patients with active colonic IBD (9 patients with Crohn's disease, CD and 7 patients with ulcerative colitis, UC) and 16 patients with macroscopically normal colon were enrolled in the study. Patients received infliximab therapy at 0, 2 and 6 weeks. At enrollment and at week 6 patients underwent unprepared flexible sigmoidoscopy, and biopsies were taken in the sigmoid colon. Endoscopic disease activity was evaluated through simplified endoscopic score for Crohn's disease (SES-CD) and by Mayo endoscopic subscore, for CD and UC, respectively. Mucosal healing was defined as the disappearance of all ulcers. Mucosal expression of 96 inflammation-related genes was evaluated by qPCR (TaqMan Low Density Array Human Immune Panel, Applied Biosystems) and gene expression data were confirmed by immunofluorescence.

Results: At baseline, 40 out of 96 genes were found to be significantly upregulated in the colonic mucosa of patients with active IBD with respect to controls; among them, the expression of 21 genes normalized after 6 weeks therapy with infliximab. We found that variations in gene expression of IL17A (Spearman's rho −0.627, p = 0.016), IL8 (Spearman's rho −0.533, p = 0.05), IL12p40 (Spearman's rho −0.589, p = 0.027), IL23p19 (Spearman's rho −0.531, p = 0.05) and NOS2A (Spearman's rho −0.542, p = 0.045) were significantly correlated with endoscopic response to infliximab therapy and with mucosal healing. At immunofluorescence, we confirmed that infliximab therapy induced a reduction in mucosal expression of IL17A, which was associated with a reduced intestinal macrophage infiltration and IL23p19 expression, but not with a reduced lymphocytic infiltrate of the colonic mucosa.

Conclusions: We demonstrate that therapy with infliximab induces a modulation in gene expression of both IL23 subunits and IL17A. These results provide further evidences on the mechanism by which this drug modulates intestinal inflammation.