The Effects of Dasatinib on IgE Receptor-Dependent Activation and Histamine Release in Human Basophils

Blood. 2008 Mar 15;111(6):3097-107. doi: 10.1182/blood-2007-08-104372. Epub 2008 Jan 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Agammaglobulinaemia Tyrosine Kinase
  • Allergens / immunology
  • Animals
  • Basophils / drug effects*
  • Basophils / immunology*
  • Basophils / metabolism
  • Cells, Cultured
  • Dasatinib
  • Female
  • Histamine Release / drug effects*
  • Histamine Release / immunology*
  • Humans
  • Interleukin-4 / biosynthesis
  • Interleukin-4 / metabolism
  • Male
  • Mice
  • Middle Aged
  • Protein Binding
  • Protein-Tyrosine Kinases / deficiency
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / pharmacology*
  • Receptors, IgE / immunology*
  • Thiazoles / pharmacology*
  • Up-Regulation

Substances

  • Allergens
  • Pyrimidines
  • Receptors, IgE
  • Thiazoles
  • Interleukin-4
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Dasatinib