To investigate the inhibitory effects of dasatinib on proliferation, function, and signaling events on CD8+T cells. MATERIALS AND
Carboxyfluorescein diacetate succinimidyl ester and 5-bromo-2-deoxyuridine were used to detect proliferation and cell cycle of CD8+T cells treated with dasatinib, respectively.
Frequency and function of viral and leukemia-antigen-specific CD8+T cells from healthy donors were measured by tetramer staining and ELISPOT assay.
Western blotting analysis was performed to detect T-cell receptor (TCR), nuclear factor kappa B (NF-kappaB) and Src signaling events in T cells treated with dasatinib or imatinib.
Dasatinib inhibited proliferation of CD8+T cells in a dose-dependent manner, which was associated with lower secretion of interferon-gamma and granzyme B, as well as with arrest of CD8+T cells in the G0/G1 phase of cell cycle.
Inhibition of CD8+T cells was proven for blood samples from a patient under dasatinib medication when compared with their T-cell status without dasatinib.
Western blotting confirmed that these effects were mediated through downregulation of the phosphorylation level of molecules from the TCR and the NF-kappaB signaling transduction cascade.
Dasatinib proved to be more potent than imatinib on Src and TCR signaling events in Jurkat T cells.
Our study demonstrated that dasatinib impaired proliferation and function of CD8+T cells via TCR and NF-kappaB signaling events without inducing apoptosis. Therefore, dasatinib might alter the graft-vs-leukemia effect and the graft-vs-host disease after allogeneic stem cell transplantation sustained by CD8+T cells.
Dasatinib might also be used as a novel immunosuppressant agent.
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Exp Hematol. 2008 Oct;36(10):1297-308
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