Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-kappa B decoy oligonucleotides.

Abstract

The Th1 and Th2 T cell responses that underlie inflammatory bowel diseases (IBDs) are likely to depend on NF-kappaB transcriptional activity. We explored this possibility in studies in which we determined the capacity of NF-kappaB decoy oligodeoxynucleotides (decoy ODNs) to treat various murine models of IBD. In initial studies, we showed that i.r. (intrarectal) or i.p. administration of decoy ODNs encapsulated in a viral envelope prevented and treated a model of acute trinitrobenzene sulfonic acid-induced (TNBS-induced) colitis, as assessed by clinical course and effect on Th1 cytokine production. In further studies, we showed that NF-kappaB decoy ODNs were also an effective treatment of a model of chronic TNBS-colitis, inhibiting both the production of IL-23/IL-17 and the development of fibrosis that characterizes this model. Treatment of TNBS-induced inflammation by i.r. administration of NF-kappaB decoy ODNs did not inhibit NF-kappaB in extraintestinal organs and resulted in CD4+ T cell apoptosis, suggesting that such treatment is highly focused and durable. Finally, we showed that NF-kappaB decoy ODNs also prevented and treated oxazolone-colitis and thus affect a Th2-mediated inflammatory process. In each case, decoy administration led to inflammation-clearing effects, suggesting a therapeutic potency applicable to human IBD.

• Authors: Stefan Fichtner-Feigl, Ivan J Fuss, Jan C Preiss, Warren Strober, Atsushi Kitani
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 11 Pg. 3057-71 (Nov 2005) ISSN: 0021-9738 [Print] United States
• PMID: 16239967 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• NF-kappaB decoy
• Oligodeoxyribonucleotides
• DNA

Topics

• Animals
• CD4-Positive T-Lymphocytes (metabolism)
• DNA (metabolism)
• Female
• Fibrosis
• Genetic Vectors
• Inflammatory Bowel Diseases (drug therapy, immunology, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mucous Membrane (cytology, metabolism)
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Oligodeoxyribonucleotides (administration & dosage, genetics, pharmacology)
• Sendai virus
• Th1 Cells (immunology)
• Th2 Cells (immunology)