Gene Expression Profiling and Response Signatures Associated With Differential Responses to Infliximab Treatment in Ulcerative Colitis

• Published in: The American journal of gastroenterology Vol. 106; no. 7; pp. 1272 - 1280
• Main Authors: Toedter, Gary, Li, Katherine, Marano, Colleen, Ma, Keying, Sague, Sarah, Huang, Chris C, Song, Xiao-Yu, Rutgeerts, Paul, Baribaud, Frédéric
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.07.2011; Wolters Kluwer Health Medical Research, Lippincott Williams & Wilkins
• Subjects: Adult; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Biopsy; Bones, joints and connective tissue. Antiinflammatory agents; Clinical trials; Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - genetics; Down-Regulation - drug effects; Female; Gastroenterology; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Agents - administration & dosage; Gastrointestinal Agents - pharmacology; Gene expression; Gene Expression Profiling; Genomes; Helper cells; Humans; Immune response (cell-mediated); Immunomodulators; Inflammation; Infliximab; Intestinal Mucosa - metabolism; Lymphocytes T; Male; Medical sciences; Middle Aged; Molecular modelling; Monoclonal antibodies; Mucosa; Other diseases. Semiology; Pharmacology. Drug treatments; Remission; Retrospective Studies; RNA, Messenger - metabolism; Signal transduction; Signal Transduction - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Th1 Cells - drug effects; Th17 Cells - drug effects; Th2 Cells - drug effects; Tumor necrosis factor- alpha; Ulcerative colitis; Up-Regulation - drug effects; Cytokine; Antipsoriatic agent; Monoclonal antibody; Gene expression; Anti-Tumor Necrosis Factor-alpha; Inflammatory disease; Immunomodulator; Treatment; Infliximab; Anticytokine; Gastroenterology; Digestive diseases; Intestinal disease; Antirheumatic agent; Immunosuppressive agent; Tumor necrosis factor α; Ulcerative colitis
• ISSN: 0002-9270; 1572-0241; 1572-0241
• DOI: 10.1038/ajg.2011.83

Infliximab has been shown to induce clinical response and remission in ulcerative colitis (UC). To characterize the biological response of patients to infliximab, we analyzed the mRNA expression patterns of mucosal colonic biopsies taken from UC patients enrolled in the Active Ulcerative Colitis Trial 1 (ACT1) study. Biopsies were obtained from 48 UC patients before treatment with 5 or 10 mg/kg infliximab, and at 8 and 30 weeks after treatment (n = 113 biopsies). Global gene expression profiling was performed using Affimetrix GeneChip Human Genome U133 Plus 2.0 arrays. Expression profiling results for selected genes were confirmed using qPCR. Infliximab had a significant effect on mRNA expression in treatment responders, with both infliximab dose and duration of treatment having an effect. Genes affected are primarily involved with inflammatory response, cell-mediated immune responses, and cell-to-cell signaling. Unlike responders, non-responders do not effectively modulate T(H₁), T(H₂), and T(H₁₇) pathways. Gene expression can differentiate placebo and infliximab responders. Analysis of mRNA expression in mucosal biopsies following infliximab treatment provided insight into the response to therapy and molecular mechanisms of non-response.