The role of plasmacytoid dendritic cells in allergic asthma

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To develop novel, more effective therapeutic strategies for the treatment of allergic asthma an improved understanding of allergen-mediated lung inflammation is needed. Recently, we identified plasmacytoid dendritic cells (pDCs) as a possible target population. In the first period of this project these pDCs were phenotypically and functionally characterized. The most important results were an increased expression of FcεRIα on peripheral blood pDCs from atopic asthmatics compared with healthy controls and an increased expression of this IgE receptor chain on endobronchial pDCs following allergen provocation. In addition, we showed for the first time the expression of IL-4 by pDCs which was upregulated in pDCs differentiated in a Th2-like cytokine milieu. These results lead to the hypothesis that in allergic asthma pDCs may function as effector cells which support or even amplify allergic inflammation. This new project is supposed to focus on this hypothesis. Therefore, the effects of crosslinking of the high affinity IgE receptor on different maturation states of pDCs will be investigated. First, naïve peripheral blood pDCs from healthy controls and allergic asthmatics will be extensively compared on mRNA, protein as well as on functional levels. To analyse more differentiated pDCs an established in vitro model will be used where IL-3 is added to naïve pDCs in the presence of a Th2-like cytokine milieu to generate so called Th2-pDCs. To analyse the in vivo relevance of this data the established human asthma model of segmental allergen challenge will be employed. Endobronchial pDCs which have been differentiated in a Th2-milieu in vivo will be isolated from bronchoalveolar lavage after allergen challenge and then will be further analysed following FcεRI-crosslinking. We expect these data will enable us to make a clear statement whether pDCs function as effector cells or as immune regulatory cells in allergic asthma. Finally, in view of the development of novel therapeutic strategies we want to identify factors whose neutralisation, inhibition or addition will increase the tolerogenic potential of Th2-pDCs and decrease their Th2-effector potential. For this attempt the in vitro model of Th2-pDCs will be performed.