1. ¹Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2. ²Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3. ³Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence: Dr JM Reuben, Department of Hematopathology, Unit 0054, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Fax: +1 713 792 4296; E-mail: jreuben@mdanderson.org

Received 27 September 2004; Accepted 3 August 2005; Published online 8 September 2005.

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.