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.

为了表达肥大细胞中的细胞因子DNA，将IL-4连接到肥大细胞特异性启动子中被注入小鼠卵。在天生的小鼠及其后代中未检测到明显转移的IL-4。因此，我们通过转基因系统将策略切换为表达突变的IL-4物种，以疫苗接种到小鼠中。用Th2型慢性皮炎的小鼠通过HAHPTEN的串行局部应用建立。用DNA疫苗编码IL-4，显性阴性诱饵IL-4或显性阴性诱饵IL-4/IL-13处理这些小鼠。 Th2型皮炎成功抑制了显性的负阴性IL-4/IL-13诱饵疫苗，而IL-4诱饵的影响有限。 IL-4激动剂或模拟FNA没有任何影响。该实验表明，显性阴性IL-4/IL-13诱饵DNA是一种用于特应性皮炎的有效治疗工具。为了评估模型鼠标的瘙痒感，我们建立了一种通过声学分析的测量系统的测量系统。这些系统声明了这些系统，这些系统可无形地刮擦该动态性皮肤病（Adopic Dermatis）模型（AD）。然后，该系统揭示了对AD小鼠的刮擦计数的有效抑制，并依赖于抗抗药性剂量。为了了解肥大细胞在AD中的作用，在细胞因子激活中评估了肥大细胞衍生的酶的作用。人类肥大细胞芝麻酶成功地处理了IL-18并产生了活性物种。这揭示了肥大细胞及其在AD皮肤病变中的Chymase排放的重要性。