Project/Area Number |
12470127
|
Research Category |
Grant-in-Aid for Scientific Research (B)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Gastroenterology
|
Research Institution | Keio University |
Principal Investigator |
NAGANUMA Makoto Keio University, School of Medicine, Instructor, 医学部, 助手 (00265810)
|
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 (20297352)
HIBI Toshifumi Keio University, School of Medicine, Professor, 医学部, 教授 (50129623)
|
Project Period (FY) |
2000 – 2001
|
Project Status |
Completed (Fiscal Year 2001)
|
Budget Amount *help |
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2001: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2000: ¥9,900,000 (Direct Cost: ¥9,900,000)
|
Keywords | interleukin-7 / interleukin-7 receptor / mucosal immunology / knock-out mice / T lymphocytes / inflammatory bowel disease / diphteria toxin |
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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