title: Predictive validity and immune cell involvement in the pathogenesis of piroxicam-accelerated colitis in interleukin-10 knockout mice.
abstract: Piroxicam administration is a method for induction of enterocolitis in interleukin-10 knockout (IL-10 k.o.) mice. The piroxicam-accelerated colitis (PAC) IL-10 k.o. model combines a dysregulated immune response against the gut microbiota with a decreased mucosal integrity. The predictive validity and pathogenic mechanisms of the model have not been thoroughly investigated. In this study, IL-10 k.o. mice received piroxicam in the chow, and model qualification was performed by examining the efficacy of prophylactic anti-IL-12/23p40 monoclonal antibody (mAb), anti-TNFα mAb, cyclosporine A (CsA) and oral prednisolone treatment. To evaluate cell involvement in the disease pathogenesis, specific cell subsets were depleted by treatment with anti-CD4 mAb, anti-CD8 mAb or clodronate-encapsulated liposomes. T cell receptor co-stimulation was blocked by CTLA4-Ig. Cytokine profiling ELISAs and calprotectin immunohistochemistry were performed on colon tissue. Treatments with anti-IL-12/23p40 mAb and CsA prevented disease in PAC IL-10 k.o. mice and reduced IFNγ, IL-17A, MPO and calprotectin levels in colon. Anti-TNFα mAb treatment caused amelioration of selected clinical parameters. No effect of prednisolone was detected. Depletion of CD8(+) cells tended to increase mortality, whereas treatment with anti-CD4 mAb or CTLA4-Ig had no significant effect on disease development. Clodronate liposome treatment induced a loss of body weight; nevertheless macrophage depletion was associated with a significant reduction in colonic pathology. In conclusion, reference drugs with known efficacy in severe inflammatory bowel disease were efficacious in the PAC IL-10 k.o. model. Our data indicate that in this model macrophages are a main driver of colitis, whereas CD4(+) cells are not.
authors.affiliation: Novo Nordisk - LIFE In Vivo Pharmacology Centre, 1870 Frederiksberg, Denmark; Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark; Department of Immunopharmacology, Novo Nordisk A/S, 2760 Maaloev, Denmark. Electronic address: KHLG@novonordisk.com.
authors.forename: Kristine
authors.initials: K
authors.lastname: Holgersen
authors.affiliation: Department of Histology, Novo Nordisk A/S, 2760 Maaloev, Denmark. Electronic address: PHKv@novonordisk.com.
authors.forename: Peter Helding
authors.initials: PH
authors.lastname: Kvist
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark. Electronic address: akh@sund.ku.dk.
authors.forename: Axel Kornerup
authors.initials: AK
authors.lastname: Hansen
authors.affiliation: Department of Immunopharmacology, Novo Nordisk A/S, 2760 Maaloev, Denmark. Electronic address: ThLH@novonordisk.com.
authors.forename: Thomas Lindebo
authors.initials: TL
authors.lastname: Holm
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage*; D004760:Enterocolitis / Q000139:chemically induced / Q000235:genetics; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D018664:Interleukin-12 / Q000276:immunology; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010894:Piroxicam / Q000008:administration & dosage / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019138:Antibodies, Blocking; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D010894:Piroxicam; D018664:Interleukin-12; D016572:Cyclosporine
keywords: Inflammatory bowel disease; Inflammatory mediators; Interleukin-10 knockout mouse; Piroxicam; Validity