Development of antagonistic Thymic Stromal Lymphopoietin (TSLP) variants and evaluation of their inhibitory properties towards asthma-associated TSLP activity by ex vivo studies employing human leukocytes

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Asthma bronchiale is one of the most common chronic diseases with increasing prevalence. The cytokine Thymic Stromal Lymphopoietin (TSLP) and its receptor TSLPR (according to the current model a heterodimer of the TSLP receptor alpha-chain and the interleukin-7 receptor alpha-chain) are critically involved in the pathogenesis of allergic asthma. This system is therefore an attractive target for specific inhibitory substances. In this project, designed on the basis of a structural model of the murine TSLPR, variants of the human TSLP with potentially antagonistic / inhibitory properties compared to the wild-type cytokine, will be recombinantly produced and characterized in a cellular model system. The activation mechanism of the TSLP receptor system is not sufficiently well understood. It will be, hence, be characterized biochemically (starting from recombinant proteins) and cell biologically (based on functionally expressed receptor variants in reporter cells) with the aim of opening up novel routes and molecular strategies for the generation of inhibitors with high affinity and efficiency.The characteristics and the application potential of the potential inhibitors will be tested in vitro on primary human lung cells. These investigations will in particular focus on TSLP reactive myeloid dendritic cells and basophilic granulocytes.