Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis
Therapeutic effect of a new immunosuppressive agent, everolimus, on interleukin-10 gene-deficient mice with colitis
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DOI：
10.1111/j.1365-2249.2007.03345.x
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发表时间：
2007-05-01
影响因子：
4.6
通讯作者：
Sawa, Y.
中科院分区：
文献类型：
--
作者：
Matsuda, C.;Ito, T.;Sawa, Y.
目前可用于炎症性肠病（IBD）患者的治疗策略数量有限。特别是，克罗恩病（CD）缓解后的维持治疗并不令人满意，需要新的方法。白细胞介素-10基因缺陷（IL-10（-/-））小鼠，一个良好的CD实验模型，发展严重的慢性结肠炎由于异常的Th 1免疫应答。依维莫司是一种新型的免疫抑制剂，是雷帕霉素靶蛋白（mTOR）的抑制剂，已成功应用于心、肝、肺和肾移植的动物模型。在本研究中，我们在IL-10（-/-）小鼠模型中检查了依维莫司治疗慢性结肠炎的疗效。对具有结肠炎临床体征的IL-10（-/-）小鼠经口给予依维莫司4周。将结肠的大体和组织学外观以及淋巴细胞的数量、表型和细胞因子产生与对照组中的这些特征进行比较。依维莫司给药4周后，结肠炎的严重程度显著降低，结肠固有层中CD 4（+）T细胞数量以及结肠淋巴细胞中IFN-γ的产生显著减少。依维莫司治疗IL-10（-/-）小鼠结肠炎可改善结肠炎，这可能是由于结肠粘膜中CD 4（+）T细胞数量减少和IFN-γ产生相关减少的结果。
A limited number of therapeutic strategies are currently available for patients with inflammatory bowel disease (IBD). In particular, the maintenance therapy after remission in Crohn's disease (CD) is not satisfactory and new approaches are needed. Interleukin-10 gene-deficient (IL-10(-/-)) mice, a well-characterized experimental model of CD, develop severe chronic colitis due to an aberrant Th1 immune response. Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), a new immunosuppressive reagent, has been used successfully in animal models for heart, liver, lung and kidney transplantation. In the present study, we examined the efficacy of everolimus in the treatment of chronic colitis in an IL-10(-/-) mouse model. Everolimus was administered orally for a period of 4 weeks to IL-10(-/-) mice with clinical signs of colitis. The gross and histological appearances of the colon and the numbers, phenotype and cytokine production of lymphocytes were compared with these characteristics in a control group. The 4-week administration of everolimus resulted in a significant decrease in the severity of colitis, together with a significant reduction in the number of CD4(+) T cells in the colonic lamina propria as well as IFN-gamma production in colonic lymphocytes. Everolimus treatment of established colitis in IL-10(-/-) mice ameliorated the colitis, probably as a result of decreasing the number of CD4(+) T cells in the colonic mucosa and an associated reduction in IFN-gamma production.