title: Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro.
abstract: The ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML and is increasingly used in the stem cell transplantation (SCT) setting. Since ABL-dependent intracellular signaling molecules are involved in T-cell activation, imatinib may affect T-cell responses in vivo, thus affecting T-cell function in CML patients, disrupting immune reconstitution after allogeneic SCT and/or impeding the graft-versus-leukemia effect. Here we demonstrate that imatinib inhibits PHA-induced proliferation of normal peripheral blood mononuclear cells at in vitro concentrations (1-5 micromol/l) representative of the pharmacological doses used therapeutically in vivo. The effect is not dependent on antigen-presenting cells because CD3/CD28-induced T-cell stimulation was similarly inhibited by imatinib. Dose-dependent inhibition of the proliferative response of purified CD8+ and CD4+ T lymphocytes to anti-CD3/CD28 was similarly observed and associated with reduction in IFN-gamma production. The inhibitory effect could not be ascribed to an increased rate of apoptosis but the expression of activation markers on CD3+ T cells was significantly reduced in the presence of imatinib (1-5 micromol/L). Inhibition of T-cell proliferation was reversible after removal of the drug from the cultures. Thus, imatinib inhibits T-cell proliferation in vitro, an effect that is APC-independent, reversible, and does not involve apoptosis induction.
authors.affiliation: Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College at Hammersmith Hospital, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Cwynarski
authors.forename: R
authors.initials: R
authors.lastname: Laylor
authors.forename: E
authors.initials: E
authors.lastname: Macchiarulo
authors.forename: J
authors.initials: J
authors.lastname: Goldman
authors.forename: G
authors.initials: G
authors.lastname: Lombardi
authors.forename: J V
authors.initials: JV
authors.lastname: Melo
authors.forename: F
authors.initials: F
authors.lastname: Dazzi
mesh_terms: D001549:Benzamides; D001773:Blood Cells; D017252:CD3 Complex / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000068877:Imatinib Mesylate; D008213:Lymphocyte Activation / Q000187:drug effects*; D016374:Oncogene Proteins v-abl / Q000037:antagonists & inhibitors; D010835:Phytohemagglutinins / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D001549:Benzamides; D017252:CD3 Complex; D016374:Oncogene Proteins v-abl; D010835:Phytohemagglutinins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate