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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 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 Citation Map 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 Google Scholar Articles by Kneidinger, M. Articles by Valent, P. PubMed PubMed Citation Articles by Kneidinger, M. Articles by Valent, P. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY The effects of dasatinib on IgE receptor–dependent activation and histamine release in human basophils Michael Kneidinger1, Uwe Schmidt2, Uwe Rix3, Karoline V. Gleixner1, Anja Vales1, Christian Baumgartner1, Christian Lupinek4, Margit Weghofer4, Keiryn L. Bennett3, Harald Herrmann1, Alexandra Schebesta2, Wayne R. Thomas5, Susanne Vrtala4, Rudolf Valenta4, Francis Y. Lee6, Wilfried Ellmeier2, Giulio Superti-Furga3, and Peter Valent1 1 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; 2 Institute of Immunology, Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria; 3 Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; 4 Division of Immunopathology, Department of Pathophysiology, Center for Physiology and Pathophysiology, Medical University of Vienna, Vienna, Austria; 5 Center for Child Health Research, University of Western Australia, Telethon Institute of Child Health Research, West Perth, Australia; and 6 Oncology Drug Discovery, Bristol-Myers Squibb, Princeton, NJ Dasatinib is a multitargeted drug that blocks several tyrosine kinases. Apart from its well-known antileukemic activity, the drug has attracted attention because of 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 IgE-mediated up-regulation of CD13, CD63, CD164, and CD203c in basophils. The effects of dasatinib were dose-dependent (IC50: 50-500 nM) and 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 in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcRI downstream targets in basophils, in-cluding Btk. Correspondingly, FcRI-mediated histamine secretion in basophils was markedly reduced in Btk knockout 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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