2000 Fiscal Year Final Research Report Summary
Development of a new therapeutic modality with antisense suppression of MAdCAM-1 gene expression for inflammatory bowel diseases
| Project/Area Number |
11670518
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Yamaguchi University School of Medicine |
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Principal Investigator |
HINODA Yuji Yamaguchi University School of Medicine, Professor, 医学部, 教授 (10165128)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIDA Tadao Sapporo Medical University School of Medicine, Research Associate, 医学部, 助手 (20305220)
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| Project Period (FY) |
1999 – 2000
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| Keywords | MAdCAM-1 / antisense oligonucleotides / TNBS-induced colitis / inflammatory bowel diseases / gene therapy |
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| Research Abstract |
Background and Aims-Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is known to be restrictedly expressed in gut associated lymphoid tissues, and its expression level increases in inflammatory bowel diseases (IBD), being a promising target molecule for IBD treatment. This study aims at clarifying the effectiveness of the antisense oligonucleotides specific for murine MAdCAM-1 against trinitrobenzenesulfonic acid (TNBS) -induced colitis. Methods-BALB/c mice were intrarectally received 1 mg of TNBS in 50% ethanol for induction of colitis and administered MAdCAM-1 antisense oligonucleotide, sense, or vehicle alone by s.c. injection. The wasting disease, histologic change, infiltration of CD4 + cell and β7 + cell, and expression of MAdCAM-1 were evaluated. Results-Administration of MAdCAM-1 antisense oligonucleotides significantly suppressed the development of TNBS-induced colitis in the clinical and histopathological aspects, compared to control oligonucleotides. Immunohistochemistry and semi-quantitative RT-PCR of the colon tissues revealed that the expression levels of MAdCAM-1 mRNA and protein were lower in mice treated with the antisense oligonucleotide than in control ones. In addition, the MAdCAM-1 antisense led to a reduction in the number of CD4 + T cells and β7 + cells in the colonic mucosa. Conclusions-The expression of MAdCAM-1 is increased on endothelial cells of the colon from TNBS-induced colitis mice and the suppression of MAdCAM-1 by antisense oligonucleotide significantly prevents the development of TNBS-induced colitis. These data suggest that the antisense suppression of MAdCAM-1 may be a new therapeutic modality for IBD.
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