Dasatinib inhibits proliferation and activation of CD8+ T-lymphocytes by down-regulation of the T-cell receptor signaling
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The novel Src/Abl inhibitor dasatinib (BMS-354825) is a promising therapeutic agent with imatinib-resistant BCR-ABL mutations in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL). However, little is known about its effects on T-cell function, especially for patients undergoing allogeneic transplantation for leukemia. Here, we demonstrate that dasatinib at a concentration of 5 nM to 250 nM inhibits the proliferation and activation of CD8+ T-lymphocytes following stimulation with phytohemagglutinin-M (PHA) and interleukin-2 (IL-2) in vitro. Proliferation of activated CD8+ T lymphocytes was almost completely inhibited by 25 nM dasatinib. Furthermore, dose-dependent inhibition of proliferation of antigen-triggered expansion of specific CD8+ T-lymphocytes was also inhibited by dasatinib and associated with the reduction in IFN-alpha and granzyme B. The inhibitory effects of dasatinib was not due to an increased rate of apoptosis but ascribed to the down-regulation of activation markers CD25, CD69 and HLA-DR in the presence of dasatinib (5 - 250 nM). Inhibition of CD8+ T-lymphocytes was partially reversible after removal of dasatinib from the cultures. Using western blotting analysis, we found that these effects are mediated at least in part by down-regulating the levels of phosphorylation of T-cell receptor (TCR) and Nuclear Factor kappa B (NF-kappa B) family members. Taken together, our study demonstrates that dasatinib impairs the CD8+ T-lymphocytes proliferation and activation in vitro via TCR and NF-kappa signal transduction without inducing apoptosis.
Subject HeadingsNuklearfaktor kappa B [GND]
CD8-positive T-lymphocytes [MeSH]
Receptors, antigen, T-cell [MeSH]