Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-κB decoy oligonucleotides
Stefan Fichtner-Feigl, … , Warren Strober, Atsushi Kitani
Stefan Fichtner-Feigl, … , Warren Strober, Atsushi Kitani
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3057-3071. https://doi.org/10.1172/JCI24792.
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Research Article Immunology

Treatment of murine Th1- and Th2-mediated inflammatory bowel disease with NF-κB decoy oligonucleotides

Abstract

The Th1 and Th2 T cell responses that underlie inflammatory bowel diseases (IBDs) are likely to depend on NF-κB transcriptional activity. We explored this possibility in studies in which we determined the capacity of NF-κB 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-κB 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-κB decoy ODNs did not inhibit NF-κB in extraintestinal organs and resulted in CD4+ T cell apoptosis, suggesting that such treatment is highly focused and durable. Finally, we showed that NF-κB 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

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Prevention and treatment of oxazolone-colitis by administration of NF-κB...
Prevention and treatment of oxazolone-colitis by administration of NF-κB decoy ODNs. (A–D) Oxazolone-colitis was induced by i.r. administration of oxazolone (Oxa) in ethanol. Mice were treated with NF-κB decoy ODNs (or scrambled ODNs) via an i.r. route (4 hours) or via an i.p. route (4 hours, 24 hours). Data shown are representative of 2 independent experiments. (A) Body weight as a percent of starting weight. Data shown are mean values ± SD derived from at least 4 mice per group and are representative of 2 independent experiments. (B) Animal survival in percent until day 3 after oxazolone administration. (C) H&E staining of representative colon cross-sections on day 3 after oxazolone administration. Magnification, ×5. (D) Histological scores shown are mean values ± SD derived from at least 4 mice per group. (E–H) Treatment of established oxazolone-colitis by administration of NF-κB decoy ODNs. Oxazolone-colitis was induced by i.r. administration of oxazolone in ethanol 4 days after skin presensitization with oxazolone. Mice were treated with NF-κB decoy ODNs (or scrambled ODNs) via an i.r. route (day 4) or via an i.p. route (days 4–6). (E) Body weight as a percent of starting weight. Data shown are mean values ± SD derived from at least 3 mice per group. (F) Animal survival in percent until day 7 after oxazolone administration. (G) H&E staining of representative colon longitudinal sections on day 7 after oxazolone administration. Magnification, ×5. (H) Histological scores shown are mean values ± SD derived from at least 3 mice per group. *P < 0.01.