Inflammatory Bowel Diseases

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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e318280292b
Original Basic Science Articles

Reduction of CD68+ Macrophages and Decreased IL-17 Expression in Intestinal Mucosa of Patients with Inflammatory Bowel Disease Strongly Correlate With Endoscopic Response and Mucosal Healing following Infliximab Therapy

Caprioli, Flavio MD, PhD*,†; Bosè, Francesca PhD; Rossi, Riccardo L. PhD§; Petti, Luciana MSc; Viganò, Chiara MD*; Ciafardini, Clorinda MSc*; Raeli, Lorenzo PhD; Basilisco, Guido MD*; Ferrero, Stefano MD||; Pagani, Massimiliano PhD§; Conte, Dario MD*; Altomare, Gianfranco MD; Monteleone, Giovanni MD, PhD**; Abrignani, Sergio MD, PhD‡,§; Reali, Eva PhD

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Background: Antibodies against tumor necrosis factor represent an effective therapy for patients with inflammatory bowel disease. Despite their successful results, the exact mechanism by which infliximab suppresses intestinal inflammation is still a matter of debate. In this study, we used a translational approach to identify the key mechanisms associated with resolution of mucosal inflammation induced by infliximab.

Methods: A total of 16 patients with active inflammatory bowel disease (9 with Crohn's disease and 7 with ulcerative colitis) and 16 controls were enrolled in the study. Patients received infliximab infusions at 0, 2, and 6 weeks. At enrollment and at week 6, patients underwent flexible sigmoidoscopy, and biopsies were taken from the sigmoid colon. RNA was extracted, and mucosal expression of 96 immune-related genes was evaluated by qRT-PCR and confirmed by immunofluorescence microscopy on tissue. Correlation between infliximab-induced gene expression modulation and endoscopic response to therapy was calculated. Lamina propria mononuclear cell apoptosis induced by infliximab was evaluated on tissue sections by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay.

Results: We found that infliximab-induced downregulation of macrophage and Th17 pathway genes was significantly associated with both endoscopic response to the therapy and achievement of mucosal healing. Importantly, the observed reduction of lamina propria CD68+ macrophages was associated with an increased rate of macrophage apoptosis.

Conclusions: The 2 mechanisms associated with infliximab-induced resolution of intestinal inflammation are the reduction of lamina propria infiltrating CD68+ macrophages and the downregulation of interleukin 17A. Moreover, the data suggest that infliximab-induced macrophage apoptosis may represent a key mechanism for the therapeutic success of anti–tumor necrosis factor antibodies.

© Crohn's & Colitis Foundation of America, Inc.

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