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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3097-3107. Prepublished online as a Blood First Edition Paper on January 7, 2008; DOI 10.1182/blood-2007-08-104372. This Article Full Text (PDF) All Versions of this Article: blood-2007-08-104372v1 111/6/3097    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kneidinger, M. Articles by Valent, P. Search for Related Content PubMed PubMed Citation Articles by Kneidinger, M. Articles by Valent, P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 2, 2007 Accepted December 30, 2007 The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils Michael Kneidinger, Uwe Schmidt, Uwe Rix, Karoline V Gleixner, Anja Vales, Christian Baumgartner, Christian Lupinek, Margit Weghofer, Keiryn L Bennett, Harald Herrmann, Alexandra Schebesta, Wayne R Thomas, Susanne Vrtala, Rudolf Valenta, Francis Y. Lee, Wilfried Ellmeier, Giulio Superti-Furga, and Peter Valent* Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria Institute of Immunology, Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria Center for Child Health Research, University of Western Australia, Telethon Institute of Child Health Research, West Perth, Australia Oncology Drug Discovery, Bristol-Myers Squibb, Princeton, NJ, United States * Corresponding author; email: peter.valent{at}meduniwien.ac.at. Dasatinib is a novel multi-targeted drug that blocks several tyrosine kinases. Apart from its well-known anti-leukemic activity, the drug has recently attracted attention because of its potential immunosuppressive and anti-inflammatory effects. We report that dasatinib at 1 µM completely blocks anti-IgE-induced histamine-release in blood basophils in healthy donors, and allergen-induced release of histamine in sensitized individuals. In addition, dasatinib inhibited FcRI-mediated release of IL-4 and the IgE-mediated upregulation of CD13, CD63, CD164, and CD203c in human basophils. The effects of dasatinib were dose-dependent (IC50 50-500 nM), and were specific for FcRI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore-induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted FcRI-dependent histamine-release and upregulation of CD-molecules in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcRI-downstream-targets in basophils, including Btk. Correspondingly, the FcRI-mediated histamine-secretion in basophils was markedly reduced in Btk knock-out mice and in a patient with Btk deficiency. However, the remaining 'low-level' mediator-secretion in Btk-deficient cells was fully blocked down again by 1 µM dasatinib. Together, these data suggest that dasatinib inhibits FcRI-mediated activation of basophils through multiple signaling molecules including Btk. Dasatinib may be an interesting agent for immunologic disorders involving Btk-dependent responses or/and FcRI-activation of basophils. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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