Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner.
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 microM 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 microM and 7.3 microM, 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 microM to 0.8 microM 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.
Seggewiss
Ruth
R
Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI), the Immunology Laboratory, NIH/DHHS, Bldg 10, CRC, Rm 4-5140, 10 Center Dr, MSC 1202, Bethesda, MD 20892, USA.
Loré
Karin
K
Greiner
Elisabeth
E
Magnusson
Magnus K
MK
Price
David A
DA
Douek
Daniel C
DC
Dunbar
Cynthia E
CE
Wiestner
Adrian
A
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001549:Benzamides; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects*; D002986:Clinical Trials as Topic; D003587:Cytomegalovirus / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D015894:Genome, Human / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D000068877:Imatinib Mesylate; D016056:Immunodominant Epitopes / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D019169:Jurkat Cells; D037181:Lectins, C-Type; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000187:drug effects; D011743:Pyrimidines / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology; D000099192:CD69 Antigens
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001549:Benzamides; D000068877:Imatinib Mesylate; D016056:Immunodominant Epitopes; D007376:Interleukin-2; D037181:Lectins, C-Type; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008565:Membrane Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D051746:ZAP-70 Protein-Tyrosine Kinase; D000099192:CD69 Antigens; C508594:IL2 protein, human; C110810:LAT protein, human; C497261:ZAP70 protein, human