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RESEARCH PRODUCT

Combining dasatinib with dexamethasone long-term leads to maintenance of antiviral and antileukemia specific cytotoxic T cell responses in vitro

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description

Maintaining graft versus leukemia (GvL) and antivirus responses of cytotoxic T cells (CTLs) while suppressing graft-versus-host disease (GvHD) remains a challenge after allogeneic bone marrow transplantation. Clinical observations indicate that combining glucocorticoids with multi-tyrosine-kinase inhibitors could be a successful therapeutic approach. We and others have shown that the BCR-ABL/SRC kinase inhibitor dasatinib may enhance or suppress T cells in vitro. In this report, we evaluated combination effects of dasatinib and dexamethasone on CD3 + and virus-specific CD8 + T cells directly ex vivo and on antigen-specific leukemia-reactive and alloreactive CD8 + T cell clones. Functional outcomes assessed included cytokine production (IL-2, IFN-γ, TNF-α), degranulation (CD107a/b), activation (CD69 upregulation), proliferation, apoptosis and necrosis induction, and signal transduction. Overall, helper CD4 + T cells were more sensitive to inhibitory effects of the drug combination than cytotoxic CD8 + T cells and were more naive than memory T cell subsets. Of note, synergistic inhibitory effects occurred in different memory but not in naive T cell subsets. The drug combination inhibited virus-specific CD8 + T cell proliferation, but left cytokine production and degranulation unaltered, which may be due to the viral memory subset composition. Dasatinib rather hampered IFN-γ secretion and cytotoxic activity of human leukocyte antigen (HLA)-reactive CTLs, whereas effector functions of leukemia-reactive CTLs were maintained or enhanced when applied long term. Our data suggest that dasatinib might modulate GvL- differently than GvHD-promoting CTLs and provide a rationale to explore the drug combination further to treat GvHD while preserving GvL and antiviral CTL responses.