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，皮肤接触接触性过敏原和刺激物是非常常见的。最近的研究表明，刺激物增加了过敏性接触性皮炎的发生，特别是对弱致敏物质。以往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)在变态反应性接触性皮炎的发病机制中起着重要作用。结果表明，MRPs是接触性变应原和透明质酸的转运体。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，研究表明，与透明质酸相互作用的ITIH5在皮肤迟发性超敏反应中起着重要作用。因此，我们想研究局部应用接触性变应原(丁香酚和甲基异噻唑酮)与可增加增强效应的物质(十二烷基硫酸钠、透明质酸和邻苯二甲酸二乙基己酯)在mdr1-/-、mrp1-/-、mrp5-/-、Itih5-/-和Itih5-//mrp5-/-敲除小鼠模型、器官型小鼠3D皮肤模型和基于HaCat的敲除转染体中的作用，以及通过免疫组织学和微阵列分析来进一步深入了解皮肤刺激物和接触性变应原在人类皮肤湿疹迟发性超敏反应的发病机制中的复杂相互作用，并建立测试系统来显示增强效应。

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.