Antisense therapy of MAdCAM-1 for trinitrobenzenesulfonic acid-induced murine colitis
Antisense therapy of MAdCAM-1 for trinitrobenzenesulfonic acid-induced murine colitis
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DOI：
10.1097/00054725-200608000-00013
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发表时间：
2006-08-01
影响因子：
4.9
通讯作者：
Hinoda, Yuji
中科院分区：
文献类型：
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作者：
Goto, Akira;Arimura, Yoshiaki;Hinoda, Yuji
背景资料：抗α 4整合素试剂那他珠单抗（natalizumab）是最有前途的抗粘附单克隆抗体之一，已被引入炎症性肠病（IBD）的临床试验。最近在使用那他珠单抗的患者中报告了致死性后果，如进行性多灶性白质脑病，因此确定α（4）整合素依赖性途径中的哪种选择性粘附分子应被靶向抑制以及IBD有效治疗所需的最小活性谱至关重要。已知粘蛋白地址素细胞粘附分子（MAdCAM）-1在肠相关淋巴组织中限制性表达，并且其表达在IBD中显著增加。本研究旨在重新评估MAdCAM-1抑制的有效性，并确定抗MAdCAM-1策略的可行性。材料和方法：从三硝基苯磺酸盐灌肠的第一天开始，将反义AlAdCAM-1寡核苷酸以1.5 mg/kg/d注射到小鼠体内，连续7天。与对照组相比，MAdCAM-1反义寡核苷酸在临床和组织病理学上显著抑制了三硝基苯磺酸盐结肠炎的发展。免疫组织化学和半定量逆转录聚合酶链反应显示，MAdCAM-1蛋白和mRNA表达在反义治疗的小鼠比对照组低。结论：MAdCAM-1的反义抑制与抗MAdCAM-1或抗α 4整合素抗体的疗效相当，可能成为IBD的一种新的治疗方法。
Background: Anti-alpha(4) integrin reagent, natalizumab, which is 1 of the most promising antiadhesion monoclonal antibodies, has been introduced into clinical trials against inflammatory bowel disease (IBD). Lethal consequences such as progressive multifocal leukoencephalopathy have recently been reported in patients using natalizumab, making it critical to determine which selective adhesion molecule in the alpha(4) integrins-dependent pathway should be targeted for inhibition and the minimal spectrum of activity required for the valid treatment of IBD. Mucosal addressin cell adhesion molecule (MAdCAM)-1 is known to be restrictedly expressed in gut-associated lymphoid tissues, and its expression dramatically increases in IBD. This study aimed to reevaluate the effectiveness of MAdCAM-1 inhibition and to determine the feasibility of anti-MAdCAM-1 strategy.Materials and Methods: Antisense AlAdCAM-1 oligonucleotides were injected into mice at 1.5 mg/kg/day for 7 consecutive days from the first day of a trinitrobenzene sulfonate enema.Results: MAdCAM-1 antisense oligonucleotides significantly suppressed the development of trinitrobenzene sulfonate colitis clinically and histopathologically compared with controls. Immunohistochemistry and semiquantitative reverse-transcription polymerase chain reaction of the colon tissues revealed that MAdCAM-1 protein and mRNA expression were lower in antisense-treated mice than in controls. In addition, MAdCAM-1 antisense treatment reduced the number Of alpha(4)beta(+)(7) lymphocytes in the inflamed colonic mucosa.Conclusions: These data suggest that antisense suppression of MAdCAM-1 is of equivalent effectiveness to that of anti-MAdCAM-1 or anti-alpha(4) integrin antibody in previous reports and could be a new therapy for IBD.