Holgersen, Kristine4; Kvist, Peter Helding3; Hansen, Axel Jacob Kornerup5; Holm, Thomas Lindebo3
1 Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, Københavns Universitet2 Section of Biomedicine, Department of Veterinary Disease Biology, Faculty of Life Sciences, Københavns Universitet3 Novo Nordisk A/S4 Section of Biomedicine, Department of Veterinary Disease Biology, Faculty of Life Sciences, Københavns Universitet5 Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, Københavns Universitet
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-TNFαmAb, 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-TNFαmAb treatment caused amelioration of selected clinical parameters. No effect of prednisolonewas detected. Depletion of CD8+ cells tended to increase mortality, whereas treatmentwith 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.
International Immunopharmacology, 2014, Vol 21, Issue 1, p. 137-147
The Faculty of Health and Medical Sciences; Inflammatory bowel disease; Interleukin-10 knockout mouse; Piroxicam; Inflammatory mediator; Validity