Development of a new therapeutic modality with antisense suppression of MAdCAM-1 gene expression for inflammatory bowel diseases

开发反义抑制 MAdCAM-1 基因表达的炎症性肠病新治疗方式

• 批准号: 11670518
• 负责人: HINODA Yuji
• 金额: $ 2.37万
• 依托单位: Yamaguchi University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670518/
• 关键词: MAdCAM-1; antisense oligonucleotides; TNBS-induced colitis; inflammatory bowel diseases; gene therapy; MAdCAM-1、; アンチセンス抑制、; TNBS腸炎、; 炎症性腸疾患、

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.

众所周知，背景和目标 - 粘膜地址分子1（MADCAM-1）是在肠道相关的淋巴UES中表达的，其明确水平在炎性肠道疾病（IBD）中增加是IBD处理的有希望的目标分子旨在阐明针对三硝基苯二氮的抗分氨酸寡核苷酸针对三硝基苯二核TNBS）诱导的结肠炎。 S.C注射疗法，组织学变化，CD4 +细胞的浸润和MadCAM-1的表达。与对照DES相比反义寡核苷酸比MADCAM-1反义导致CD4 + T CELS和β7 + LS的数量减少了色彩粘膜中的结论 - MadCam-1的表达增加了TNBS的山地渗透细胞。反义寡核苷酸对MADCAM-1的抑制可以明显阻止发育中的TNBS诱导的结肠炎。

项目成果

日野田裕治他2名: "消化管と免疫-MAdCAM-1"Annual Review 消化器. 68-71 (1999)

Yuji Hinoda 和其他 2 人：“胃肠道和免疫 - MAdCAM-1”胃肠病学年度评论 68-71 (1999)。

日野田裕治: "消化管と免疫-MAdCAM-1"Annual Review消化器. 68-71 (1999)

Yuji Hinoda：“胃肠道和免疫-MAdCAM-1”胃肠病学年度评论 68-71 (1999)。

Hinoda Y.et al.: "MAdCAM-1"Annual Review of Digestive Organs. 68-71 (1999)

Hinoda Y.等人：“MAdCAM-1”消化器官年度回顾。

Goto A.et al.: "Preventive effect of MAdCAM-1 antisense oligonucleotide on trinitrobenzene-sulfonic acid-induced murine colitis."Gut. (in press). (2001)

Goto A.等人：“MAdCAM-1 反义寡核苷酸对三硝基苯磺酸诱导的小鼠结肠炎的预防作用。”肠道。

Goto A. et al.: "Preventive effect of MAdCAM-1 antisense oligonucleotide on trinitrobenzenesul fonic acid-induced murine colitis."Gut. (in press). (2001)

Goto A. 等人：“MAdCAM-1 反义寡核苷酸对三硝基苯磺酸诱导的小鼠结肠炎的预防作用。”Gut。