title: 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.
abstract: 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.
authors: Unit of Gastroenterology II, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.
authors: Flavio
authors: F
authors: Caprioli
authors: Francesca
authors: F
authors: Bosè
authors: Riccardo L
authors: RL
authors: Rossi
authors: Luciana
authors: L
authors: Petti
authors: Chiara
authors: C
authors: Viganò
authors: Clorinda
authors: C
authors: Ciafardini
authors: Lorenzo
authors: L
authors: Raeli
authors: Guido
authors: G
authors: Basilisco
authors: Stefano
authors: S
authors: Ferrero
authors: Massimiliano
authors: M
authors: Pagani
authors: Dario
authors: D
authors: Conte
authors: Gianfranco
authors: G
authors: Altomare
authors: Giovanni
authors: G
authors: Monteleone
authors: Sergio
authors: S
authors: Abrignani
authors: Eva
authors: E
authors: Reali
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D004724:Endoscopy; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000069285:Infliximab; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014945:Wound Healing; D000097382:CD68 Molecule
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005765:Gastrointestinal Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000069285:Infliximab; D020381:Interleukin-17; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule