title: The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils.
abstract: 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 microM 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 FcepsilonRI-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 (IC(50): 50-500 nM) and specific for FcepsilonRI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore-induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted FcepsilonRI-dependent histamine release in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcepsilonRI downstream targets in basophils, including Btk. Correspondingly, FcepsilonRI-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 muM dasatinib. Together, these data suggest that dasatinib inhibits FcepsilonRI-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 FcepsilonRI activation of basophils.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Kneidinger
authors.forename: Uwe
authors.initials: U
authors.lastname: Schmidt
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Anja
authors.initials: A
authors.lastname: Vales
authors.forename: Christian
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Christian
authors.initials: C
authors.lastname: Lupinek
authors.forename: Margit
authors.initials: M
authors.lastname: Weghofer
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schebesta
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Thomas
authors.forename: Susanne
authors.initials: S
authors.lastname: Vrtala
authors.forename: Rudolf
authors.initials: R
authors.lastname: Valenta
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Wilfried
authors.initials: W
authors.lastname: Ellmeier
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D000293:Adolescent; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000485:Allergens / Q000276:immunology; D000818:Animals; D001491:Basophils / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D000069439:Dasatinib; D005260:Female; D006636:Histamine Release / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D015847:Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017455:Receptors, IgE / Q000276:immunology*; D013844:Thiazoles / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000485:Allergens; D011743:Pyrimidines; D017455:Receptors, IgE; D013844:Thiazoles; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000069439:Dasatinib