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.

信号转导和转录激活因子6（STAT 6）在IL-4和IL-13的转录激活中起重要作用，可能参与了接触性皮炎（CD）和特应性皮炎（AD）的发病机制。本文报道了用抗DNP-IgE单克隆抗体诱导的AD模型小鼠，其接触性超敏反应和IgE介导的迟发相反应在STAT 6缺陷（STAT 6 ~）小鼠中显著降低。因此，我们假设，合成的双链DNA与STATE的高亲和力可以引入体内作为诱饵顺式元件结合转录因子，并阻止基因激活的CD或AD的发病和发展，从而提供有效的治疗CD和AD。经抗DNP-IgE抗体致敏后，转染STAT 6诱骗寡核苷酸（decoy oligodeoxynucleotides，ODN），不仅能显著抑制STAT 6与细胞核的结合，而且能显著抑制细胞的接触超敏反应和晚期反应。组织学分析显示，在STAT 6诱饵ODN转染小鼠中，水肿以及中性粒细胞和嗜酸性粒细胞的浸润均显著减少。为了研究STATE诱饵ODN的体内作用机制，我们采用体外肥大细胞培养系统。转染STAT 6 decoy ODN的肥大细胞与IgE受体结合后，组胺释放正常，但细胞因子（TNF-α、IL-6）释放明显减少。我们在此报道了首次成功地体内转移STATE诱饵ODN以减少晚期反应，从而为CD和特应性皮炎提供了一种新的治疗策略。

项目成果

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