TY - JOUR
T1 - The Effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils
AU - Kneidinger, M.
AU - Schmidt, U.
AU - Rix, U.
AU - Gleixner, K.V.
AU - Vales, A.
AU - Baumgartner, C.
AU - Lupinek, C.
AU - Weghofer, M.
AU - Bennett, K.L.
AU - Herrmann, H.
AU - Schebesta, A.
AU - Thomas, Wayne
AU - Vrtala, S.
AU - Valenta, R.
AU - Lee, F.Y.
AU - Ellmeier, W.
AU - Superti-Furga, G.
AU - Valent, P.
PY - 2008
Y1 - 2008
N2 - 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 FcϵRI-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 FcϵRI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore–induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted FcϵRI-dependent histamine release in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcϵRI downstream targets in basophils, in-cluding Btk. Correspondingly, FcϵRI-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 FcϵRI-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 FcϵRI activation of basophils.
AB - 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 FcϵRI-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 FcϵRI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore–induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted FcϵRI-dependent histamine release in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several FcϵRI downstream targets in basophils, in-cluding Btk. Correspondingly, FcϵRI-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 FcϵRI-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 FcϵRI activation of basophils.
U2 - 10.1182/blood-2007-08-104372
DO - 10.1182/blood-2007-08-104372
M3 - Article
SN - 0006-4971
VL - 111
SP - 3097
EP - 3107
JO - Blood
JF - Blood
IS - 6
ER -