1. Fc Receptor-mediated Effector Function Contributes to the Therapeutic Response of Anti-TNF Monoclonal Antibodies in a Mouse Model of Inflammatory Bowel Disease
- Author
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Annette Schwartz Sterman, Bryant Shaughn H, Pim J. Koelink, Gijs R. van den Brink, Manon E. Wildenberg, Peter Bousquet, Jochen Salfeld, Bradford L. McRae, Alon D. Levin, Rajesh V. Kamath, Geert R. D'Haens, Igor Mikaelian, Amsterdam institute for Infection and Immunity, Amsterdam Gastroenterology Endocrinology Metabolism, Graduate School, Gastroenterology and Hepatology, and Tytgat Institute for Liver and Intestinal Research
- Subjects
Male ,0301 basic medicine ,medicine.drug_class ,Arthritis ,Mice, SCID ,Receptors, Fc ,Antibodies, Monoclonal, Humanized ,Monoclonal antibody ,Sensitivity and Specificity ,Inflammatory bowel disease ,Certolizumab ,Etanercept ,Mice ,Random Allocation ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,Adalimumab ,Animals ,Medicine ,Molecular Targeted Therapy ,Mice, Inbred BALB C ,Tumor Necrosis Factor-alpha ,business.industry ,Gastroenterology ,General Medicine ,Inflammatory Bowel Diseases ,medicine.disease ,Arthritis, Experimental ,Immunohistochemistry ,Infliximab ,Disease Models, Animal ,030104 developmental biology ,Mice, Inbred DBA ,Immunology ,Colitis, Ulcerative ,Female ,030211 gastroenterology & hepatology ,Tumor necrosis factor alpha ,business ,Biomarkers ,medicine.drug - Abstract
Background and Aims: 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. Conclusion: 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.
- Published
- 2016