title: Dasatinib inhibits the proliferation and function of CD4+CD25+ regulatory T cells.
abstract: CD4+CD25+ regulatory T cells (Tregs) can influence various immune responses. Little is known about the effects of the Abl/Src kinase inhibitor dasatinib on Tregs which regulate anti-tumor/leukaemia immune responses. The present study demonstrated that dasatinib inhibited proliferation of Tregs and CD4+CD25- T cells in a dose-dependent manner, which was associated with the decreased production of corresponding cytokines. Treatment of Tregs with dasatinib inhibited the suppressive capacity of Tregs. The mechanisms of this inhibition included arrest of cells in the G0/G1 phase of cell cycle, down-regulation of the transcription factor forkhead box P3, glucocorticoid-induced tumour necrosis factor receptor and the cytotoxic T lymphocyte associated protein 4 as well as inhibition of signaling events through Src and nuclear factor kappaB. Dasatinib showed an inhibitory effect on the proliferation and function of both Tregs and CD4+CD25- T cells at therapeutically relevant concentrations of the drug. Clinical administration of dasatinib might influence not only the graft-versus-leukaemia effect but also the graft-versus-host-disease in patients receiving dasatinib after allogeneic stem cell transplantation and/or donor lymphocytes infusion as the function of both Tregs and effector T cells are hampered in a similar way by dasatinib.
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Fei
authors.initials: F
authors.lastname: Fei
authors.forename: Yingzhe
authors.initials: Y
authors.lastname: Yu
authors.forename: Anita
authors.initials: A
authors.lastname: Schmitt
authors.forename: Markus Thomas
authors.initials: MT
authors.lastname: Rojewski
authors.forename: Baoan
authors.initials: B
authors.lastname: Chen
authors.forename: Marlies
authors.initials: M
authors.lastname: Götz
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Donald
authors.initials: D
authors.lastname: Bunjes
authors.forename: Michael
authors.initials: M
authors.lastname: Schmitt
mesh_terms: D000704:Analysis of Variance; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D015847:Interleukin-4 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D018124:Receptors, Tumor Necrosis Factor; D013844:Thiazoles; D015847:Interleukin-4; D007371:Interferon-gamma; D000069439:Dasatinib