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

J. Clin. Invest. 2005 Nov; 115(11):3057-71

Speaker: 林建達                 Time: 2005/12/21 14:00-15:00

Commentator: 翁舷誌 老師       Place: Room 601

Abstract:

   Inflammatory bowel disease (IBDs) is a group of chronic disorders that causes inflammation or ulceration in the small and large intestines. Most often, IBD is classified either as ulcerative colitis or Crohn's disease. While ulcerative colitis affects the inner lining of the colon and rectum, Crohn's disease extends into the deeper layers of the intestinal wall. It is a chronic condition and may recur at various times over a lifetime. Recent studies of the idiopathic IBDs strongly suggest that these diseases are due to inappropriate and/or excessive responses to antigens present in the normal bacterial microflora. 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 rectum and colon. In recent years, a great number of murine models of mucosal inflammation mimicking these diseases have been described, leading to a profound increase in our understanding of their immunologic bases. One such model, hapten-induced colitis in mice caused by intrarectal (i.r.) instillation of trinitrobenzene sulfonic acid (TNBS-colitis) is a Th1 T cell–mediated colitis that captures many of the features of Crohn disease. On the other hand, a second hapten-induced colitis in mice (oxazolone-colitis), caused by i.r. instillation of oxazolone , reproduces many of the features of ulcerative colitis . The Th1 and Th2 T cell responses that underlie IBDs are likely to depend on NF-κB transcriptional activity. The authors explored this possibility in studies in which they determined the capacity of NF-κB decoy oligodeoxynucleotides (decoy ODNs) to treat various murine models of IBD. In each case, decoy administration led to inflammation-clearing effects, suggesting a therapeutic potency

applicable to human IBD.

References:

1. Heller, F., Fuss, I.J., Nieuwenhuis, E.E., Blumberg, R.S., and Strober, W. 2002. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells.Immunity 17:629–638.

2. Schreiber, S., Nikolaus, S., and Hampe, J. 1998. Activation of nuclear factor kappa B inflammatory bowel disease. Gut 42:477–484.