Project 1: The Th1 and Th2 T cell responses that underlie inflammatory bowel diseases (IBD) are likely to depend on NF-kB transcriptional activity. We explored this possibility in studies in which we determined the capacity of NF-kB decoy oligodeoxynucleotides (decoy ODN) to treat various murine models of IBD. In initial studies we showed that i.r. (intra-rectal) or i.p. (intra-peritoneal) administration of decoy ODN encapsulated in a viral envelope prevented and treated an acute model of TNBS-colitis, as assessed by clinical course and effect on Th1 cytokine production. In further studies we showed that NF-kB decoy ODN was also an effective treatment of a chronic model of TNBS-colitis and this case inhibited 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-kB decoy ODN did not inhibit NF-kB in extra-intestinal organs and resulted in CD4+ T cell apoptosis, suggesting that such treatment is highly focused and durable. Finally, we showed that NF-kB decoy ODN also prevented and treated oxazolone-colitis and thus affects a Th2-mediated inflammatory process. In each case decoy administration led to inflammation clearing effects suggesting a therapeutic potency applicable to human IBD. Project 2: The Th1 and Th2 T cell responses that underlie inflammatory inflammatory and autoimmune diseases are likely to depend on NF-kB transcriptional activity. We explored this possibility in studies in which we determined the capacity of NF-kB decoy oligodeoxynucleotides (decoy ODN) to treat various murine models of mucosal inflammation. In initial studies we showed that i.r. (intra-rectal) or i.p. (intra-peritoneal) administration of decoy ODN encapsulated in a viral envelope prevented and treated an acute model of TNBS-colitis, as assessed by clinical course and effect on Th1 cytokine production. In further studies we showed that NF-kB decoy ODN was also an effective treatment of a chronic model of TNBS-colitis and in this case inhibited 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-kB decoy ODN did not inhibit NF-kB in extra-intestinal organs and resulted in CD4+ T cell apoptosis, suggesting that such treatment is highly focused and durable. Finally, we showed that NF-kB decoy ODN also prevented and treated oxazolone-colitis and thus affects a Th2-mediated inflammatory process. In each case decoy administration led to inflammation clearing effects suggesting a therapeutic potency applicable to human inflammatory diseases, especially inflammatory bowel disease.
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