利多卡因促进特应性皮炎调节性T细胞分化的作用及机制

Skin barrier dysfunction, constant antigenic stimulation of Staphylococcus aureus colonization and regulatory T cell (Treg) dysfunction contribute to the pathogenesis of atopic dermatitis (AD). In view of the good curative effect of lidocaine in the clinical practice with severe AD patients, we carried out the research. It was proven that lidocaine could up-regulate the expression of Treg in vivo and promote the differentiation of Treg from Naive CD4+ T cells in vitro, which tended to be related with Smad3 signaling pathway. The suppressive function of Treg and the specific pathway of Treg upregulation by lidocaine remained unknown. Our amis of the research are as follows: 1) We plan to veryfy the suppresive function of Treg on the effective CD4+ T cells proliferation and to investigate the expression of inflammatory factors such as IFN-γ, IL-4, IL-17E they relaesed; 2) We aim to invetigate whether the up-regulated Treg had co-expression of T-bet and GATA3 and whether lidocaine had effect on Treg plasticity; 3)We intend to block Smad3/TGF-β with the specific inhibitor SIS3 and compare the difference of Treg differentiation. In addition, we planed to explore the NF-кB signaling pathway to define the specific pathway.

皮肤屏障功能破坏、金葡菌定植引起抗原持续刺激、调节性T细胞（Treg）抑制功能失衡进而导致持续性炎症反应是特应性皮炎（AD）发病的关键因素。本项目组在应用利多卡因静脉封闭治疗重症AD取得较好疗效的基础上，证实利多卡因在体内可上调Treg的表达水平；在体外可促进初始化CD4+T细胞向Treg分化，而且可能与smad3途径有关。那么由利多卡因上调的Treg的抑制功能是否正常？它上调Treg表达的机制是什么？本研究旨在①探讨上调的的Treg是否抑制效应性CD4+T细胞的增殖，及其所释放的IFN-γ，IL-4及IL-17E的表达水平，验证Treg的抑制功能；②探讨上调的Treg中是否共表达T-bet及GATA3，明确利多卡因可否影响Treg分化的可塑性；③在体外使用SIS3特异性阻断Smad3/TGF-β通路，比较利多卡因调节Treg分化的差异，并探索NF-кB信号通路，明确作用途径。

本研究首次发现利多卡因可促进Treg细胞的分化并明确其机制，为利多卡因应用于AD的临床治疗提供了又一重要的理论依据。这一研究成果发表于J Allergy Clin Immunol上（IF=13.081）。并由编辑部发表重点述评，认为利多卡因是治疗重度AD的新方法。本项目组多年致力于AD的基础与临床研究，2017年由《Allergy》特邀发表述评《Current status in diagnosis of atopic dermatitis in China》，阐述目前中国AD的诊疗现状。本项目成果作为主要申报内容获得2017年度（第十六届）上海医学科技奖二等奖（第一完成单位）；2018年中华医学科技奖二等奖（第一完成单位）。.本项目共计发表标注本项目的SCI论文3篇（总计影响因子为24.274）。举办全国性学术会议2次，参加国际会议2次，参加国内学术交流10次以上。培养博士研究生5名（已毕业）。