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.

背景与目的粘蛋白地址素细胞粘附分子-1（MAdCAM-1）在肠道相关淋巴组织中表达受限，在炎症性肠病（IBD）中表达增强，是治疗IBD的一个有希望的靶分子。本研究旨在阐明小鼠MAdCAM-1特异性反义寡核苷酸对三硝基苯磺酸（TNBS）诱导的结肠炎的有效性。方法BALB/c小鼠直肠内接受溶于50%乙醇的1 mg TNBS以诱导结肠炎，并通过s.c.注射评价消瘦性疾病、组织学变化、CD 4+细胞和β7 +细胞浸润以及MAdCAM-1表达。结果：与对照寡核苷酸相比，MAdCAM-1反义寡核苷酸在临床和组织病理学方面显著抑制TNBS诱导的结肠炎的发展。免疫组化和半定量RT-PCR结果显示，反义寡核苷酸治疗组小鼠结肠组织中MAdCAM-1 mRNA和蛋白的表达水平均低于对照组。此外，MAdCAM-1反义导致结肠粘膜中CD 4 + T细胞和β7 +细胞的数量减少。结论TNBS诱导的结肠炎小鼠结肠内皮细胞上MAdCAM-1的表达增加，反义寡核苷酸抑制MAdCAM-1可显著防止TNBS诱导的结肠炎的发展。这些数据表明，MAdCAM-1的反义抑制可能是IBD的一种新的治疗方式。

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)。

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。

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 trinitrobenzenesulfonic 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。