| Co-Investigator(Kenkyū-buntansha) |
WATANABE Mamoru Tokyo Medical & Dental Univ., Dept of Medicine, Professor, 医学部, 教授 (10175127)
FUNAKOSHI Shinsuke Keio University, School of Medicine, Instructor, 医学部, 助手
HIBI Toshifumi Keio University, School of Medicine, Professor, 医学部, 教授 (50129623)
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| Research Abstract |
Chronic inflammatory bowel disease (IBD) is a inflammatory disorder of the intestine with unknown etiology, and therefore no specific treatment is available for the management of IBD. We have already reported that interleukin-7 (IL-7) is produced by intestinal epithelial cells, especially goblet cells, and the IL-7/IL-7 receptor (IL-7R) system plays an important role in regulating the T lymphocyte proliferation, activation and function in the intestine (J Clin Invest 95: 2945, 1995). Based on these findings, we generated IL-7 transgenic mice and found that these mice developed chronic colitis resembling human ulcerative colitis, and demonstrated the involvement mucosal CD4 positive T lymphocytes in the intestinal inflammation (J Exp Med 187: 389, 1998).
In this study, we developed the new therapeutic approach targeting the activated mucosal immune cells, i.e., IL-7 receptor (IL-7R) positive T lymphocytes. We first crossed TCRα^<-/-> mice, which spontaneously develop chronic colitis similar to human ulcerative colitis, with IL-7R^<-/-> mice and these mice did not develop colitis. We next administered anti-IL-7R antibody and anti-IL-7R-saporin to TCRα^<-/-> mice. These treatment improved intestinal inflammation. On the basis of these results, we synthesized diphtheria toxin conjugated IL-7 (DAB389-IL-7) to eliminate IL-7R positive activated T lymphocytes specifically. To deliver DAB389-IL-7 fusion protein into the intestinal lumen, we are now developing new drug delivery system by introducing DAB389-IL-7 expressing vector to E. coli from intestinal flora. These specific immune therapy may provide the potential therapeutic advantages in the treatment of human IBD.
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