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Division of Immunopathology
Department of Pathophysiology and Allergy Research
Center of Pathophysiology, Infectiology & Immunology

Medical University of Vienna

Vienna General Hospital, AKH, 3Q
Waehringer Guertel 18-20
A-1090 Vienna, Austria
 

IgE-dependent activation of human basophils and mast cells: dissection of novel pathways and development of new diagnostic and pharmacologic concepts [Valent]

Project summary 

Mast cells and basophils are effector cells of allergic reactions. Both cells store mediators of allergy in their granules and release these mediators in response to IgE receptor cross-linking provoked by allergens or other stimuli. The ability to respond to an allergen (releasability) is pre-determined by genetic factors, expression of surface antigens, and the type of external ligand(s). The release-reaction itself is related to activation of several signal transduction pathways, expression and activation of membrane enzymes, and translocation of granules to the cell surface. However, little is known so far about the complex biochemical basis and molecular mechanisms underlying cell activation.
During the past few years, a number of activation-linked surface antigens expressed in human basophils and mast cells have been identified. Several of these antigens, like CD63, are upregulated on IgE-dependent cell activation, and have been employed to develop in vitro allergy test assays. During the course of our SFB project, we found that CD203c is a novel reliable and sensitive marker of in vitro basophil activation provoked by natural or recombinant allergens. Moreover, we found that combining CD63 and CD203c in one assay may be preferable and may lead to an optimal diagnostic tool in allergology. The value of this new approach will be determined in the consecutive phase of this SFB project by employing the assay in allergic patients before and during immunotherapies or treatment with conventional drugs. In addition, the assay will be used to measure the in vitro response of basophils to novel inhibitory drugs that block signal transduction molecules and thereby basophil activation. Another goal for the third project period is to define the functional role of CD203c and of other upregulated surface antigens in IgE-dependent reactions of basophils.
The most interesting pharmacologic inhibitor of allergen-induced activation and histamine release in basophils identified in this project is dasatinib, a multikinase-targeting agent that is already used in clinical practice. This drug was found to completely block anti-IgE- and allergen-induced histamine release and cytokine secretion as well as allergen-induced upregulation of CD203c, CD63, and other antigens on basophils at pharmacologic concentrations. Chemical proteomic profiling and Western blotting revealed that a major binding-partner and target of dasatinib in basophils is Bruton´s tyrosine kinase (Btk). Other binding partners of dasatinib (e.g. Src or Lyn) were also identified in these studies. During the next project period, the functional role of each dasatinib-binding partner and their role as potential therapeutic targets will be determined using knock out cells, siRNA, and additional specific inhibitors. Respective targeted drugs blocking Src, Lyn, or other signaling molecules, are available, and will be applied alone or in combination to block basophil activation. In fact, a major aim in this project period will be to obtain cooperative (synergistic) effects of targeted drugs on in vitro basophil activation provoked by (recombinant) allergens or anti-IgE.