title: Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia.
abstract: Although imatinib mesylate (IM) is highly effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia (CML), it is known to suppress T-cell proliferation in vitro. As cytokines are required for T-cell proliferation, we investigated the effects of IM on cytokine synthesis by T cells of CML patients by assessing cytokine synthesis by activated CD4+ and CD8+ T cells in vitro. The activation of T cells in the whole blood of IM-treated patients (CML-IM) with Staphylococcus enterotoxin B resulted in significantly lower percentages of CD4+ T cells that synthesized interleukin 2 (P = 0.017), interferon-gamma (P = 0.010), and tumor necrosis factor-alpha (P = 0.009) than did the activated T cells of control subjects. The addition of exogenous IM to the cultures of peripheral blood mononuclear cells of CML-IM patients reduced Th1 cytokine synthesis by the CD4+ T cells. Furthermore, IM therapy at clinical doses suppressed the tyrosine phosphorylation of ZAP70. These findings suggest that inhibition of ZAP70 signaling pathway and suppression of Th1 cytokine synthesis by CD4+ T cells required the presence of IM at the time of T-cell activation through the T-cell receptor.
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: H
authors.initials: H
authors.lastname: Gao
authors.forename: B-N
authors.initials: BN
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.forename: N J
authors.initials: NJ
authors.lastname: Donato
authors.forename: J E
authors.initials: JE
authors.lastname: Cortes
authors.forename: H M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: J M
authors.initials: JM
authors.lastname: Reuben
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D016022:Case-Control Studies; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D004768:Enterotoxins / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology*; D008213:Lymphocyte Activation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D014443:Tyrosine; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D016207:Cytokines; D004768:Enterotoxins; D010879:Piperazines; D011743:Pyrimidines; C026066:enterotoxin A, Staphylococcal; D014443:Tyrosine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human