The impact of asthma on dendritic cell development.. (DC IN ASTHMA)
The impact of asthma on dendritic cell development; analysis at the cellular and the molecular level
(DC IN ASTHMA)
Date du début: 1 juil. 2014,
Date de fin: 30 juin 2016
Allergic asthma is a chronic inflammatory disease of the airways and a worldwide problem. Dendritic cells (DC) have a key role in the development of this disease, making them interesting targets for therapy. Novel asthma therapies could involve interference with the development and relative abundance of functionally specialized lung DC subsets. Allergen exposure drastically changes airway DC subset distribution and preliminary experiments show effects on myeloid bone marrow progenitors. We hypothesize that DC precursor development, selection and differentiation choices are affected by allergen-induced airway inflammation and this might affect the outcome of the pulmonary immune response to allergens. Here, we aim to elucidate how asthma affects the distribution and differentiation capacity of DC progenitors/precursors at the cellular and the molecular level. In a novel house dust mite (HDM)-driven mouse asthma model, we will analyze HDM-induced changes in the distribution of bone marrow, circulating and lung-resident progenitors/precursors. In vitro development of progenitors/precursors isolated from HDM-exposed and control mice will be compared to identify imprinting effects on differentiation capacity. To find the mechanism by which asthma alters or imprints DC development from progenitors/precursors, HDM and asthma-associated cytokines will be added to in vitro DC differentiation cultures to evaluate their effects on development. The most promising candidates will be tested by analyzing DC development in HDM-exposed knockout mice and 50/50 mixed bone marrow chimeras. Moreover, gene expression profiles from progenitors/precursors isolated from HDM-exposed and control mice will be compared to identify new regulatory networks. Finally, findings will be validated in in vitro human DC differentiation cultures and human immune system mice. These data will help to define crucial DC development pathways during asthma that may be amenable to therapeutic intervention.
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