Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA
Treatment of T cell-dependent experimental colitis in SCID mice by local administration of an adenovirus expressing IL-18 antisense mRNA
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DOI：
10.4049/jimmunol.168.1.411
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发表时间：
2002-01-01
影响因子：
4.4
通讯作者：
Neurath, MF
中科院分区：
文献类型：
--
作者：
Wirtz, S;Becker, C;Neurath, MF
最近的研究表明，IL-18是一种增强IFN-γ产生的多效性细胞因子，由克罗恩病患者的肠上皮细胞和固有层细胞产生。在这项研究中，我们表明，IL-18是强烈表达的肠上皮细胞在克罗恩病的小鼠模型诱导的CD 62 L（+）CD 4（+）T细胞转移到SCID小鼠。为了在该模型中特异性下调IL-18表达，我们构建了表达IL-18反义mRNA的E1/E3缺失腺病毒，表示为Ad-asIL-18，并证明了这种载体在结肠衍生的DLD-1细胞和RAW264.7巨噬细胞中下调IL-18表达的能力。局部给药的Ad-asIL-18载体的SCID小鼠建立结肠炎导致上皮细胞的转导，并引起结肠炎活动的显着抑制，如通过新开发的结肠炎内镜分析系统进行评估。此外，用Ad-asIL-18治疗诱导了组织学结肠炎活性的显著抑制，并引起了粘膜IFN-γ产生的抑制，而脾T细胞的IFN-γ产生不受影响。总之，这些数据表明IL-18在T细胞依赖性结肠炎小鼠模型的效应期中的重要作用，并表明靶向IL-18表达的策略可用于治疗克罗恩病患者。
Recent studies have shown that IL-18, a pleiotropic cytokine that augments IFN-gamma production, is produced by intestinal epithelial cells and lamina propria cells from patients with Crohn's disease. In this study, we show that IL-18 is strongly expressed by intestinal epithelial cells in a murine model of Crohn's disease induced by transfer of CD62L(+)CD4(+) T cells into SCID mice. To specifically down-regulate IL-18 expression in this model, we constructed an E1/E3-deleted adenovirus expressing IL-18 antisense mRNA, denoted Ad-asIL-18, and demonstrated the capacity of such a vector to down-regulate IL-18 expression in colon-derived DLD-1 cells and RAW264.7 macrophages. Local administration of the Ad-asIL-18 vector to SCID mice with established colitis led to transduction of epithelial cells and caused a significant suppression of colitis activity, as assessed by a newly developed endoscopic analysis system for colitis. Furthermore, treatment with Ad-asIL-18 induced a significant suppression of histologic colitis activity and caused suppression of mucosal IFN-gamma production, whereas IFN-gamma production by spleen T cells was unaffected. Taken together, these data indicate an important role for IL-18 in the effector phase of a T cell-dependent murine model of colitis and suggest that strategies targeting IL-18 expression may be used for the treatment of patients with Crohn's disease.