title: Fc Receptor-mediated Effector Function Contributes to the Therapeutic Response of Anti-TNF Monoclonal Antibodies in a Mouse Model of Inflammatory Bowel Disease.
abstract: OBJECTIVE
  Anti-tumour necrosis factor [TNF] monoclonal antibodies [infliximab, adalimumab] induce complete mucosal healing in a proportion of patients with Crohn's disease whereas a TNF receptor fusion protein [etanercept] is not effective and the anti-TNF F[ab']2 fragment [certolizumab] shows a very low rate of complete mucosal healing. In contrast, all four TNF-neutralising drugs have demonstrated efficacy in the treatment of rheumatoid arthritis. These observations suggest that factors other than neutralisation of TNF may contribute to clinical outcomes in Crohn's disease. Here we tested the hypothesis that Fc receptor [FcR]-mediated effects may contribute to the therapeutic response of anti-TNF antibodies in inflammatory bowel disease.
  
  
  METHODS
  We modified an IgG2c mouse anti-TNF antibody that binds the high-affinity FcRs to generate an IgG1 isotype with strongly diminished binding. We examined the therapeutic effects of both antibodies in the T cell transfer model of inflammatory bowel disease and the collagen-induced arthritis model.
  
  
  RESULTS
  The IgG2c anti-TNF antibody prevented colonic inflammation in the T cell transfer model of colitis, whereas the IgG1 anti-TNF did not. Conversely, both the IgG2c and IgG1 anti-TNFs were similarly effective in reducing the severity of articular inflammation in mouse collagen-induced arthritis.
  
  
  CONCLUSIONS
  These data support the concept that the mechanism of action for TNF-neutralising drugs may differ across immune-mediated diseases and, potentially, between therapeutics within a particular disease. Our data suggest a specific role of Fc-mediated immune regulation in the resolution of intestinal inflammation by anti-TNF monoclonal antibodies.
authors.affiliation: Abbvie Bioresearch Center, Worcester, MA, USA.
authors.forename: Bradford L
authors.initials: BL
authors.lastname: McRae
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Alon D
authors.initials: AD
authors.lastname: Levin
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Manon E
authors.initials: ME
authors.lastname: Wildenberg
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Pim J
authors.initials: PJ
authors.lastname: Koelink
authors.affiliation: Abbvie Bioresearch Center, Worcester, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Bousquet
authors.affiliation: Abbvie Bioresearch Center, Worcester, MA, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Mikaelian
authors.affiliation: Abbvie Bioresearch Center, Worcester, MA, USA.
authors.forename: Annette Schwartz
authors.initials: AS
authors.lastname: Sterman
authors.affiliation: Abbvie Bioresearch Center, Worcester, MA, USA.
authors.forename: Shaughn
authors.initials: S
authors.lastname: Bryant
authors.affiliation: Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: D'Haens
authors.affiliation: Abbvie Bioresearch Center, Worcester, MA, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kamath
authors.affiliation: Abbvie Bioresearch Center, Worcester, MA, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Salfeld
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands g.r.vandenbrink@amc.nl.
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D011897:Random Allocation; D011961:Receptors, Fc / Q000187:drug effects* / Q000378:metabolism; D012680:Sensitivity and Specificity; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D011961:Receptors, Fc; D014409:Tumor Necrosis Factor-alpha
keywords: Anti-TNF; Fc receptor; IBD