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Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner

Seggewiss, R., Lore, K., Greiner, E., Magnusson, M. K., Price, David, Douek, D. C., Dunbar, D. C. and Wiestner, A. 2005. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 105 (6) , pp. 2473-2479. 10.1182/blood-2004-07-2527

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Abstract

The tyrosine kinase inhibitor imatinib (imatinib, STI571, Glivec, and 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 10 μM imatinib. Furthermore, antigen-triggered expansion of CD8+ T cells in response to immunodominant cytomegalovirus (CMV) and Epstein-Barr virus (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 inhibitory concentration 50% (IC50) of 5.4 μM and 7.3 μM, respectively; interleukin 2 (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 adenosine triphosphate (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 μM to 0.8 μM 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 after transplantation should be investigated in clinical trials.

Item Type: Article
Status: Published
Schools: Medicine
Publisher: American Society of Hematology
ISSN: 0006-4971
Date of First Compliant Deposit: 5 May 2016
Date of Acceptance: 12 November 2004
Last Modified: 04 Jun 2017 09:06
URI: http://orca.cf.ac.uk/id/eprint/90448

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