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Effects of the mutant cytokine therapy in atopic dermatitis

突变细胞因子治疗特应性皮炎的效果

基本信息

批准号：
18591242
负责人：
MIZUTANI Hitoshi
金额：
$ 2.45万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

To express cytokine DNA in mast cells, IL-4 ligated to a mast cell specific promoter was injected to mouse eggs. No obvious transferred IL-4 was detected in the born mice and their offspring. Therefore, we switched strategy to express mutant IL-4 species by transgenic system to vaccination to mouse.Mice with Th2 type chronic dermatitis were established with serially topical application of hapten. These mice were treated with DNA vaccine coding IL-4, dominant-negative decoy IL-4 or dominant-negative decoy IL-4/IL-13. Th2 type dermatitis was successfully suppressed dominant negative IL-4/IL-13 decoy vaccination, and limited effects with IL-4 decoy. IL-4 agonist or mock FNA showed no effects. This experiment revealed dominant-negative IL-4/IL-13 decoy DNA is a potent therapeutic tool for atopic dermatitis.To evaluate the itching sensation of model mouse, we established a measuring system of scratching movement by acoustic analysis.This system declared invisibly rapid scratching behavior of the atopic dermatitis (AD) model mouse. Then, this system revealed effective suppression of the scratching counts of AD mouse with oral administration of anti-histamine dose dependently.To know the roles of mast cells in AD, the mast cell derived enzymes were evaluated in cytokine activation. The human mast cell chymase processed IL-18 successfully and generated an active species. This revealed importance of mast cells and their chymase discharge in AD skin lesions.

为了在肥大细胞中表达细胞因子DNA，将连接到肥大细胞特异性启动子的IL-4注射到小鼠卵中。在出生小鼠及其子代中未检测到明显的IL-4转移。因此，我们将转基因表达突变型IL-4的策略改为免疫小鼠，通过连续局部应用半抗原建立Th 2型慢性皮炎小鼠模型。用编码IL-4、显性负性诱饵IL-4或显性负性诱饵IL-4/IL-13的DNA疫苗治疗这些小鼠。Th 2型皮炎被成功抑制，显性阴性IL-4/IL-13诱饵疫苗接种，IL-4诱饵的作用有限。IL-4激动剂或模拟FNA显示无作用。本实验通过建立一种利用声分析技术检测小鼠搔抓运动的方法，观察了小鼠搔抓运动的变化，并对小鼠搔抓运动的变化规律进行了研究，结果表明，显性负性IL-4/IL-13诱骗DNA是一种有效的治疗工具。本研究通过观察肥大细胞衍生酶在细胞因子激活中的作用，探讨肥大细胞在AD发病中的作用。人肥大细胞糜酶成功地处理IL-18并产生活性物质。这揭示了肥大细胞及其糜酶分泌在AD皮损中的重要性。