A trial of gene therapy for contact allergy and atopic dermatitis

接触性过敏和特应性皮炎的基因治疗试验

• 批准号: 13670869
• 负责人: YOKOZEKI Hiroo
• 金额: $ 2.05万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670869/
• 关键词: contact dermatitis; atopic dermatitis; Th2 cytokines; Gene Therapy; STAT6; IgE; 接触アレルギー; Th2; サイトカイン; ハプテン; ランゲルハンス細胞; 遅発型反応

Signal Transducers and Activators of Transcription 6 (STAT6) play a crucial role in the transactivation of IL-4 and IL-13 which might be involved in the pathogenesis of contact dermatitis (CD) and atopic dermatitis (AD). We herein reported that the contact hypersensitivity and IgE mediated late phase reaction significantly decreased in STAT6 deficient (STAT6~) mice in AD model mice induced by intravenous injection of monoclonal anti-DNP-IgE antibody and subsequent skin testing with dinitrofluorobenzene (DNFB). We therefore hypothesized that synthetic double-stranded DNA with a high affinity for STATE could be introduced in vivo as decoy cis elements to bind the transcriptional factor and to block the gene activation of contributing the onset and progression of CD or AD, thus providing effective therapy for CD and AD. Treatment by the transfection of STAT6 decoy oligodeoxynucleotides (ODN), but not scramble decoy ODN after the sensitization by anti-DNP-IgE antibody, had a significantly inhibitory effect on not only STATE binding to nuclei but also on the conact hypersensitivity and late phase response. A histological analysis revealed that both edema and the infiltration of neutrophils and eosinophils significantly decreased in STAT6 decoy ODN transfected mice. To examine the mechanism of the in viva effect of STATE decoy ODN, we employed an in vitro mast cells culture system. After IgE receptor engagement, mast cells transfected by STAT6 decoy ODN exhibited normal histamine release, but their cytokine release (TNF-a, IL-6) markedly decreased. We herein report the first successful in viva transfer of STATE decoy ODN to reduce the late phase reaction thereby providing a new therapeutic strategy for CD and atopic dermatitis.

转录6（STAT6）的信号换能器和活化剂在IL-4和IL-13的反式激活中起着至关重要的作用，这可能参与接触性皮炎（CD）和特应性皮炎（AD）的发病机理。我们在此报告说，在静脉注射单克隆抗DNP-IgE抗体诱导的AD模型小鼠的STAT6缺乏（Stat6〜）小鼠中，接触性超敏反应和IgE介导的后期反应显着降低，并用DINITOROROOBENZENE（DNFB）进行了随后的皮肤测试。因此，我们假设可以在体内引入具有高亲和力的合成双链DNA作为诱饵CIS元素以结合转录因子并阻止促进CD或AD进展的基因激活，从而提供有效的治疗，从而提供有效的治疗用于CD和AD。通过抗DNP-IgE抗体敏化后，通过转染STAT6诱饵寡脱氧核苷酸（ODN）的治疗，而不是争夺诱饵ODN，对状态与核与核的结合不仅具有显着抑制作用。组织学分析表明，在STAT6诱饵ODN转染的小鼠中，嗜中性粒细胞和嗜酸性粒细胞的水肿和嗜中性粒细胞的浸润显着降低。为了检查状态诱饵ODN的体内效应的机制，我们采用了体外肥大细胞培养系统。在IgE受体互动后，通过STAT6诱饵ODN转染的肥大细胞表现出正常的组胺释放，但其细胞因子释放（TNF-A，IL-6）显着降低。我们在这里报告了第一个成功的州诱饵ODN的成功转移，以减少后期反应，从而为CD和特应性皮炎提供新的治疗策略。

项目成果

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