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

来源:临床研究杂志 作者:Stefan Fichtner-Feigl, Ivan J. Fuss, Jan C. Preiss 2007-5-11
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摘要: AbstractThe Th1 and Th2 T cell responses that underlie inflammatory bowel diseases (IBDs) are likely to depend on NF-B transcriptional activity。 administration of decoy ODNs encapsulated in a viral envelope prevented and treated a model of acute trinitrobenzene sulfonic acid–induced (TNBS-induc......


Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.

    Abstract

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

    Introduction

Results of recent studies of the idiopathic inflammatory bowel diseases (IBDs; Crohn disease and ulcerative colitis) strongly suggest that these diseases are due to inappropriate and/or excessive responses to antigens present in the normal bacterial microflora (1-6). Crohn disease is characterized by a transmural, granulomatous inflammation occurring anywhere in the alimentary canal but is usually centered in the terminal ileum and ascending colon; ulcerative colitis, in contrast, is marked by a superficial inflammation causing epithelial cell destruction (ulceration) that is centered in the rect