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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. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-07-2527v1 105/6/2473    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Seggewiss, R. Articles by Wiestner, A. Search for Related Content PubMed PubMed Citation Articles by Seggewiss, R. Articles by Wiestner, A. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Imatinib inhibits T-cell receptor–mediated T-cell proliferation and activation in a dose-dependent manner Ruth Seggewiss, Karin Loré, Elisabeth Greiner, Magnus K. Magnusson, David A. Price, Daniel C. Douek, Cynthia E. Dunbar, and Adrian Wiestner From the Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), the Immunology Laboratory and Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), the Laboratory of Medicinal Chemistry, the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, MD; and the Departments of Hematology, Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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