Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro.
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.
Cwynarski
K
K
Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College at Hammersmith Hospital, London, UK.
Laylor
R
R
Macchiarulo
E
E
Goldman
J
J
Lombardi
G
G
Melo
J V
JV
Dazzi
F
F
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
D001549:Benzamides; D017252:CD3 Complex; D016374:Oncogene Proteins v-abl; D010835:Phytohemagglutinins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate