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

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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.