| Budget Amount *help |
¥17,100,000 (Direct Cost: ¥17,100,000)
Fiscal Year 2000: ¥8,100,000 (Direct Cost: ¥8,100,000)
Fiscal Year 1999: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Research Abstract |
Inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disorder of 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, as well as stromal cells in thymus and bone marrow, 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 established 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). Moreover, we demonstrated that CD 4 positive T lymphocytes with particular Vβ usage were preferentially activated in the inflamed lesions of CD (Clin Immunol Immunopathol 78 : 130, 1996).
In the present study, we assessed the therapeutic effect of a synthetic mimetic of CD4 designed to mimic both the sequence and conformation of complementarity-determining region 3 of murine CD4 V1 domain (rD-mPGPtide) in a mouse colitis model using immunization with 2,4,6-trinitrobenzene sulfonic acid (TNB). Adiministration of the rD-mPGPtide but not control scrambled peptide could suppress severe inflammation in the chronic colitis mouse model (Eur J Immunol 29 : 355, 1999).
Based on these results, we are now developing the new therapeutic approach targeting the activated mucosal immune cells, i.e., diphtheria toxin conjugated IL-7 and Saporin conjugated anti-Mac-1 antibody by collaboration with Prof.Daniel K Podolsky and Prof.Micheal B Brenner at Harvard Medical School. These specific immune therapy may provide the potential therapeutic advantages in the treatment of human IBD.
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