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

在日常生活中，皮肤同时暴露于接触性过敏原和刺激物是非常常见的。最近的研究提供了证据，刺激物增加过敏性接触性皮炎的发展，特别是对弱致敏物质。本项目前期研究表明，多药耐药相关蛋白（MRPs）MDR 1、MRP 1和MRP 5以及ITI重链5（ITIH 5）在变应性接触性皮炎的发病机制中起重要作用。研究表明，MRP作为接触性过敏原和透明质酸的转运蛋白发挥作用。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，已经证明与透明质酸相互作用的ITIH 5在皮肤的迟发型超敏反应中起重要作用。因此，我们想研究局部应用接触性过敏原的效果（丁香酚和甲基异噻唑啉酮），不含或与可增加增效作用的物质合用（月桂基硫酸钠、透明质酸和邻苯二甲酸二乙基己酯）在Mdr 1-/-、Mrp 1-/-、Mrp 5-/-、Itih 5-/-和Itih 5-/-/Mrp 5-/-敲除小鼠模型中的作用，器官型鼠3D皮肤模型和基于HaCat的敲减转染子，从这些研究中，我们期望进一步了解皮肤刺激物和接触性过敏原在人类皮肤湿疹性迟发型超敏反应发病机制中的复杂相互作用，建立试验系统，以观察增强效应。

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.