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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2473-2479.
Prepublished online as a Blood First Edition Paper on November 30, 2004; DOI 10.1182/blood-2004-07-2527.
 Previous Article | Next Article 
Submitted July 6, 2004
Accepted November 12, 2004
Imatinib inhibits T-cell receptor mediated T-cell proliferation and activation in a dose-dependent manner
Ruth Seggewiss, Karin Lore, Elisabeth Greiner, Magnus K Magnusson, David A Price, Daniel C Douek, Cynthia E Dunbar*, and Adrian Wiestner
Hematology Branch, NHLBI, NIH/DHHS, Bethesda, MD, USA
Immunology Laboratory, Vaccine Research Center, NIAD, NIH/DHHS, Bethesda, MD, USA
Laboratory of Medicinal Chemistry, NIDDK, NIH/DHHS, Bethesda, MD, USA
Department of Hematology, Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland
Human Immunology Section, Vaccine Research Center, NIAD, NIH/DHHS, Bethesda, MD, USA
* Corresponding author; email: dunbarc{at}nhlbi.nih.gov.
The tyrosine kinase inhibitor imatinib (STI571, Gleevec®) is increasingly used in patients undergoing allogeneic transplantation for leukemia. However, little is known regarding its potential immunoregulatory effects. Here, we investigate the effect of imatinib on T-cell receptor (TCR)-mediated activation of human T-cells. Following stimulation with the anti-CD3 antibody 12F6, proliferation of activated T-cells was almost completely inhibited by 10µM imatinib. Furthermore, antigen-triggered expansion of CD8+ T-cells in response to immunodominant CMV and EBV peptides was significantly reduced. Up-regulation of the activation markers CD25 and CD69 in response to TCR cross-linking was suppressed by imatinib at a mean IC50 of 5.4µM and 7.3µM, respectively; IL-2 production was also impaired. Analysis of the TCR-induced signaling cascade showed that imatinib substantially reduced tyrosine phosphorylation of ZAP70 and LAT in response to activation through the TCR. Sequence comparisons of all 90 tyrosine kinase genes in the human genome for homology in the ATP binding pocket identified LCK, which is required for ZAP70 activation, as a likely target for imatinib. The IC50 for LCK inhibition by imatinib was 0.6-0.8µM in an in vitro tyrosine kinase assay. In summary, imatinib can interfere with T-cell activation in vitro and its impact on the frequency of opportunistic infections and graft-versus-host or graft-versus-leukemia reactions post-transplantation should be investigated in clinical trials.
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