The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils.
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.
Kneidinger
Michael
M
Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
Schmidt
Uwe
U
Rix
Uwe
U
Gleixner
Karoline V
KV
Vales
Anja
A
Baumgartner
Christian
C
Lupinek
Christian
C
Weghofer
Margit
M
Bennett
Keiryn L
KL
Herrmann
Harald
H
Schebesta
Alexandra
A
Thomas
Wayne R
WR
Vrtala
Susanne
S
Valenta
Rudolf
R
Lee
Francis Y
FY
Ellmeier
Wilfried
W
Superti-Furga
Giulio
G
Valent
Peter
P
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
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