Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro

Abstract

The ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML and is increasingly used in the stem cell transplantation (SCT) setting. Since ABL-dependent intracellular signaling molecules are involved in T-cell activation, imatinib may affect T-cell responses in vivo, thus affecting T-cell function in CML patients, disrupting immune reconstitution after allogeneic SCT and/or impeding the graft-versus-leukemia effect. Here we demonstrate that imatinib inhibits PHA-induced proliferation of normal peripheral blood mononuclear cells at in vitro concentrations (1-5 micromol/l) representative of the pharmacological doses used therapeutically in vivo. The effect is not dependent on antigen-presenting cells because CD3/CD28-induced T-cell stimulation was similarly inhibited by imatinib. Dose-dependent inhibition of the proliferative response of purified CD8+ and CD4+ T lymphocytes to anti-CD3/CD28 was similarly observed and associated with reduction in IFN-gamma production. The inhibitory effect could not be ascribed to an increased rate of apoptosis but the expression of activation markers on CD3+ T cells was significantly reduced in the presence of imatinib (1-5 micromol/L). Inhibition of T-cell proliferation was reversible after removal of the drug from the cultures. Thus, imatinib inhibits T-cell proliferation in vitro, an effect that is APC-independent, reversible, and does not involve apoptosis induction.

Imatinib mesylate selectively impairs expansion of memory cytotoxic T cells without affecting the control of primary viral infections

“…In accordance with published data, 9,10 we found that imatinib inhibited 3 H-thymidine incorporation. Earlier studies have suggested that the reduced expansion was largely due to inhibition of cell-cycle activity.…”

“…8 In addition, several in vitro studies using T cells isolated from human peripheral blood have demonstrated a dose-dependent reduction of T-cell proliferation in the presence of imatinib. 1,9,10 These results raise the possibility that imatinib could affect normal immune functions through TK inhibition. TKs play a prominent role in T-cell receptor (TCR) and B-cell receptor (BCR) signal transduction, and, thus, it is conceivable that imatinib may interfere with this process.…”

“…The involvement of ABL kinases in TCR signal transduction and T-cell viability is further confirmed by ABL-deficient mice, which show thymic and splenic atrophy and substantial T-and B-cell lymphopenia. 9,11 However, there are currently no indications that c-ABL may be regulated differently in naive and memory CTLs. In contrast, another study has reported that in memory CD8 ϩ T cells Lck expression is increased and associated with the CD8 coreceptor, whereas in naive CD8 ϩ T cells Lck is homogenously distributed in the cytoplasm and must first be recruited to the CD8 coreceptor upon TCR stimulation.…”

“…1,9,10 Since peripheral-blood lymphocytes were used as responders in these experiments, proliferating cells may largely represent antigen-experienced effector and memory T cells. 32 In contrast, naive CD8 ϩ T cells, expressing homing receptors for secondary lymphoid organs, 32 are resident in the secondary lymphoid organs and therefore may have been excluded from these analyses.…”

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

“…These agents cause growth arrest, apoptosis and decreased cell migration in EGFR-expressing basal keratinocytes through inhibition of the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)-Akt and Janus kinase (JAK)-STAT (signal transducer and activator of transcription) pathways 98 . Finally, imatinib has significant but pleiotropic effects on the immune system, including inhibition of T-cell proliferation and activation [99][100][101][102][103] , impaired monocyte 104 and natural killer cell 105 function, and increased antigen presentation by dendritic cells 106 . The target or targets underlying these effects are unclear, but may include ABL1/2 and/or the T-cell-receptor-associated tyrosine kinases ZAP70 and SYK.…”