title: Combining dasatinib with dexamethasone long-term leads to maintenance of antiviral and antileukemia specific cytotoxic T cell responses in vitro.
abstract: 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.
authors: Immune Recovery Section, Department of Internal Medicine II, Division of Hematology, Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Germany.
authors: Thomas
authors: T
authors: Nerreter
authors: Eva
authors: E
authors: Distler
authors: Carolin
authors: C
authors: Köchel
authors: Hermann
authors: H
authors: Einsele
authors: Wolfgang
authors: W
authors: Herr
authors: Ruth
authors: R
authors: Seggewiss-Bernhardt
mesh_terms: D000956:Antigens, Viral / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003587:Cytomegalovirus / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D000069439:Dasatinib; D003907:Dexamethasone / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006680:HLA Antigens / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000956:Antigens, Viral; D016207:Cytokines; D006680:HLA Antigens; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; D013844:Thiazoles; D003907:Dexamethasone; D000069439:Dasatinib