Goto Akira, Arimura Yoshiaki, Shinomura Yasuhisa, Imai Kohzoh, Hinoda Yuji
First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Sapporo, Japan.
Inflamm Bowel Dis. 2006 Aug;12(8):758-65. doi: 10.1097/00054725-200608000-00013.
Anti-alpha4 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 alpha4 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.
Antisense MAdCAM-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.
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 alpha4beta7 lymphocytes in the inflamed colonic mucosa.
These data suggest that antisense suppression of MAdCAM-1 is of equivalent effectiveness to that of anti-MAdCAM-1 or anti-alpha4 integrin antibody in previous reports and could be a new therapy for IBD.
抗α4整合素试剂那他珠单抗是最有前景的抗黏附单克隆抗体之一，已被引入针对炎症性肠病（IBD）的临床试验。最近有报道称，使用那他珠单抗的患者出现了诸如进行性多灶性白质脑病等致命后果，因此确定α4整合素依赖性途径中的哪种选择性黏附分子应作为抑制靶点以及有效治疗IBD所需的最小活性谱至关重要。已知黏膜地址素细胞黏附分子（MAdCAM）-1在肠道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抑制MAdCAM-1的有效性，并确定抗MAdCAM-1策略的可行性。
从三硝基苯磺酸灌肠的第一天起，以1.5毫克/千克/天的剂量连续7天将反义MAdCAM-1寡核苷酸注射到小鼠体内。
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结肠炎的发展。结肠组织的免疫组织化学和半定量逆转录聚合酶链反应显示，反义处理的小鼠中MAdCAM-1蛋白和mRNA表达低于对照组。此外，MAdCAM-1反义处理减少了炎症结肠黏膜中α4β7淋巴细胞的数量。
这些数据表明，MAdCAM-1的反义抑制与先前报道中的抗MAdCAM-1或抗α4整合素抗体具有同等效力，可能成为IBD的一种新疗法。
