Augmentation of the contact allergen-mediated sensitization in Mdr1-/-, Mrp1-/-, Mrp5-/-, Itih5-/- and Itih5-/-/Mrp5-/- mouse models as well as in murine and human 3D skin models

在 Mdr1-/-、Mrp1-/-、Mrp5-/-、Itih5-/- 和 Itih5-/-/Mrp5-/- 小鼠模型以及小鼠和人类 3D 皮肤模型中增强接触过敏原介导的致敏作用

• 批准号: 335120387
• 负责人: Professor Dr. Jens Malte Baron
• 金额: --
• 依托单位: Klinik für Dermatologie und Allergologie - Hautklinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/335120387?language=en
• 关键词: Augmentation; contact; allergen; mediated; sensitization

In daily life, combined skin exposure to contact allergens and irritants is very common. Recent studies provide evidence that irritants augment the development of allergic contact dermatitis, especially against weak sensitizing substances. Previous studies to this project showed an important role of multidrug resistance related proteins (MRPs) MDR1, MRP1 and MRP5 as well as ITI heavy chain 5 (ITIH5) in the pathogenesis of allergic contact dermatitis. It was shown that MRPs function as transporters of contact allergens and hyaluronan. Irritants can regulate the expression of the transport proteins in skin cells through the release of cytokines. In addition, it has been demonstrated that ITIH5 that interacts with hyaluronan plays an important role in delayed type hypersensitivity responses of the skin. Therefore, we want to study the effect of topically applied contact allergens (eugenol and methylisothiazolinone) without or in combination with substances that could increase augmentation effects (sodium lauryl sulfat, hyaluronan and diethylhexyl phthalate) in Mdr1-/-, Mrp1-/-, Mrp5-/-, Itih5-/- and Itih5-/-/Mrp5-/- knockout mouse models, organotypic murine 3D skin models and HaCat based knockdown transfectants employing immunohistologic- and microarray analyses.From these studies we anticipate further insight in the complex interaction of skin irritants and contact allergens in the pathogenesis of eczematous delayed type hypersensitivity responses of the human skin and the establishment of test systems to visualize augmentation effects.

在日常生活中，皮肤同时接触接触性过敏原和刺激物是很常见的。最近的研究提供的证据表明，刺激物会加剧过敏性接触性皮炎的发展，特别是对于弱致敏物质。该项目之前的研究表明，多药耐药相关蛋白 (MRP) MDR1、MRP1 和 MRP5 以及 ITI 重链 5 (ITIH5) 在过敏性接触性皮炎的发病机制中发挥重要作用。研究表明，MRP 具有作为接触性过敏原和透明质酸转运蛋白的功能。刺激物可以通过释放细胞因子来调节皮肤细胞中转运蛋白的表达。此外，已证明与透明质酸相互作用的ITIH5在皮肤迟发型超敏反应中发挥重要作用。因此，我们想要研究局部应用的接触性过敏原（丁子香酚和甲基异噻唑啉酮）在不使用或与可增加增强效果的物质（十二烷基硫酸钠、透明质酸和邻苯二甲酸二乙基己酯）的情况下对 Mdr1-/-、Mrp1-/-、 Mrp5-/-、Itih5-/- 和 Itih5-/-/Mrp5-/- 敲除小鼠模型，采用免疫组织学和微阵列分析的器官型小鼠 3D 皮肤模型和基于 HaCat 的敲除转染子。从这些研究中，我们期望进一步了解皮肤刺激物和接触过敏原在人类皮肤湿疹迟发型超敏反应的发病机制中的复杂相互作用，并建立测试系统以可视化增强效果。

项目成果

Inter-α-Trypsin Inhibitor Heavy Chain 5 (ITIH5) Is a Natural Stabilizer of Hyaluronan That Modulates Biological Processes in the Skin

α-胰蛋白酶抑制剂重链 5 (ITIH5) 是透明质酸的天然稳定剂，可调节皮肤的生物过程

• DOI: 10.1159/000509371
• 发表时间: 2020-08-14
• 期刊: Skin Pharmacology and Physiology
• 影响因子: 2.7
• 作者: Sebastian Huth;L. Huth;Y. Marquardt;K. Fietkau;E. Dahl;P. Esser;Stefan F. Martin;R. Heise;H. Merk;J. Baron
• 通讯作者: J. Baron