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: Kristine Holgersen, Peter Helding Kvist, Axel Kornerup Hansen, Thomas Lindebo Holm
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 21 Issue 1 Pg. 137-47 (Jul 2014) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 24797915 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Blocking
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Piroxicam
• Interleukin-12
• Cyclosporine

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, adverse effects)
• Antibodies, Blocking (administration & dosage)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cells, Cultured
• Cyclosporine (administration & dosage)
• Enterocolitis (chemically induced, genetics)
• Female
• Humans
• Interleukin-10 (genetics)
• Interleukin-12 (immunology)
• Lymphocyte Depletion
• Macrophages (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Animal
• Piroxicam (administration & dosage, adverse effects)
• Tumor Necrosis Factor-alpha (immunology)