A trial of gene therapy for contact allergy and atopic dermatitis

信号转导和转录激活因子6 （STAT6）在IL-4和IL-13的反激活中起关键作用，可能参与接触性皮炎（CD）和特应性皮炎（AD）的发病机制。我们在此报道，静脉注射抗dnp -IgE单克隆抗体并随后用二硝基氟苯（DNFB）皮肤试验诱导AD模型小鼠中STAT6缺陷（STAT6~）小鼠的接触过敏和IgE介导的晚期反应显著降低。因此，我们假设可以将合成的具有高STATE亲和力的双链DNA作为诱导性顺式元件引入体内，结合转录因子并阻断促成CD或AD发病和进展的基因激活，从而为CD和AD提供有效的治疗。经抗dnp - ige抗体致敏后转染STAT6诱饵寡脱氧核苷酸（decoy oligodeoxynucleotides， ODN），而不转染scramble诱饵核苷酸（scramble decoy ODN），不仅对STATE与细胞核的结合有显著抑制作用，而且对接触超敏反应和晚期反应也有显著抑制作用。组织学分析显示，转染STAT6诱饵ODN的小鼠水肿、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。与IgE受体结合后，转染STAT6诱饵ODN的肥大细胞组胺释放正常，但细胞因子（TNF-a、IL-6）释放明显降低。我们在此报告了首次成功的体外转移STATE诱饵ODN以减少晚期反应，从而为CD和特应性皮炎提供了新的治疗策略。

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.