Predictive validity and immune cell involvement in the pathogenesis of piroxicam-accelerated colitis in interleukin-10 knockout mice

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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.
Original languageEnglish
JournalInternational Immunopharmacology
Issue number1
Pages (from-to)137-147
Number of pages11
Publication statusPublished - 2014

ID: 117779601