Induktion einer Hautsensibilisierung nach Kontakt mit Chemikalien über nicht klassische alternative Mechanismen: Charakterisierung der Schlüsselereignisse ausgehend vom Molekül bis hin zur Gewebereaktion
Zusammenfassung der Projektergebnisse
Fragrance compounds remain the most commonly detected allergens, although they are typically moderate sensitizers. Exposure sources are numerous, e.g. terpene fragrances such as limonene, linalool and citronellol are ingredients in up to 60% of cosmetic products, household products and occur naturally in essential oils. In contrast to the parent molecules, certain air-oxidation products of them are categorized as strong sensitizers based on predictive animal models. With respect to contact allergy in humans, publications reporting high prevalence (approx. 4%) of patch test reactions to mixtures containing definite amounts of limonene-hydroperoxides (lim-OOHs) or linalool-hydroperoxides together with parent molecules are constantly increasing. However, human data and a quantitative link between the amounts of hydroperoxides in fragrance-containing products and human sensitization is unclear. Thus, the questions remains what the cause is and therefore it is important to evaluate whether certain cells or individuals are highly responsive to these molecules. Specifically, intensive characterizations of the radicals generated in the cells exposed and involved in the activation of the immune response, both under normal conditions and diseased conditions, will give us a better insight into what is happening and would lead to a better understanding of the issue. R-OOHs are believed to initiate the process leading to sensitization and allergic contact dermatitis (ACD) through mechanisms involving radical intermediates. Thus, radical intermediates, keratinocytes and dendritic cells (DC) may act in concert to initiate the process. Here, we evaluated their sensitization potential and potency for the first time in vitro, using a coculture method, consisting of HaCaT keratinocytes and THP-1 cells as surrogate model (COCAT). The obtained results are comparable with their sensitization potency ranking in predictive animal models. Further evaluation of the individual DC activation profiles in the context of keratinocytes by ROOHs found very specific profiles, with regard to frequency, specificity and magnitude of response. Using 2D and 3D coculture models, consisting of dendritic cells in coculture with keratinocytes, remarkable differences were found between the limonene-OOHs, namely limonene-1-OOH was clearly stronger than limonene-2-OOH. Elucidation whether susceptibility factors arising from diseased keratinocytes are implicated in the activation of DC showed comparable susceptibility of keratinocytes from atopic and non-atopic individuals. In sum, the analysis of a complete set of important hydroperoxides indicates that very small structural alterations in the hydroperoxides are translated into specific DC responses. In addition, we provide more insights into the amounts of hydroperoxides that are able to activate DC and induce sensitization in humans.
Projektbezogene Publikationen (Auswahl)
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Sensitization potential and potency of terpene hydroperoxides in the cocultured activation test method. Contact Dermatitis, 2019. 81(2):97-103
Hennen, J., Silva e Sousa, M., Sahli, F., Lichter, J., Lepoittevin, J.P., Gimenez-Arnau, E., and Blömeke, B.
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Understanding the skin sensitization capacity of ascaridole: a combined study of chemical reactivity and activation of the innate immune system (dendritic cells) in the epidermal environment. Arch Toxicol, 2019. 93(5):1337-1347
Sahli, F., Silva e Sousa, M., Vileno, B., Lichter, J., Lepoittevin, J.P., Blömeke, B., and Gimenez- Arnau, E.
