PMID- 23466625
OWN - NLM
STAT- MEDLINE
DCOM- 20130909
LR  - 20151119
IS  - 1873-2399 (Electronic)
IS  - 0301-472X (Linking)
VI  - 41
IP  - 7
DP  - 2013 Jul
TI  - Combining dasatinib with dexamethasone long-term leads to maintenance of 
      antiviral and antileukemia specific cytotoxic T cell responses in vitro.
PG  - 604-614.e4
LID - S0301-472X(13)00061-1 [pii]
LID - 10.1016/j.exphem.2013.02.013 [doi]
AB  - 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-gamma, TNF-alpha), 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-gamma 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.
CI  - Copyright (c) 2013 ISEH - Society for Hematology and Stem Cells. Published by 
      Elsevier Inc. All rights reserved.
FAU - Nerreter, Thomas
AU  - Nerreter T
AD  - Immune Recovery Section, Department of Internal Medicine II, Division of 
      Hematology, Comprehensive Cancer Center Mainfranken, University Hospital of 
      Wurzburg, Germany.
FAU - Distler, Eva
AU  - Distler E
FAU - Kochel, Carolin
AU  - Kochel C
FAU - Einsele, Hermann
AU  - Einsele H
FAU - Herr, Wolfgang
AU  - Herr W
FAU - Seggewiss-Bernhardt, Ruth
AU  - Seggewiss-Bernhardt R
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130304
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (Antigens, Viral)
RN  - 0 (Cytokines)
RN  - 0 (HLA Antigens)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Thiazoles)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - RBZ1571X5H (Dasatinib)
SB  - IM
MH  - Antigens, Viral/immunology
MH  - Apoptosis/drug effects
MH  - Cell Degranulation/drug effects
MH  - Cell Division/drug effects
MH  - Cells, Cultured/drug effects/immunology
MH  - Cytokines/biosynthesis
MH  - Cytomegalovirus/immunology
MH  - Cytotoxicity, Immunologic/drug effects
MH  - Dasatinib
MH  - Dexamethasone/*pharmacology
MH  - Drug Evaluation, Preclinical
MH  - Drug Synergism
MH  - HLA Antigens/immunology
MH  - Herpesvirus 4, Human/immunology
MH  - Humans
MH  - K562 Cells
MH  - Lymphocyte Activation/drug effects
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Pyrimidines/*pharmacology
MH  - Receptors, Antigen, T-Cell/immunology
MH  - Signal Transduction/drug effects
MH  - T-Cell Antigen Receptor Specificity
MH  - T-Lymphocyte Subsets/*drug effects/immunology
MH  - T-Lymphocytes, Cytotoxic/drug effects/immunology
MH  - T-Lymphocytes, Helper-Inducer/drug effects/immunology
MH  - Thiazoles/*pharmacology
EDAT- 2013/03/08 06:00
MHDA- 2013/09/10 06:00
CRDT- 2013/03/08 06:00
PHST- 2012/11/15 00:00 [received]
PHST- 2013/02/12 00:00 [revised]
PHST- 2013/02/22 00:00 [accepted]
PHST- 2013/03/08 06:00 [entrez]
PHST- 2013/03/08 06:00 [pubmed]
PHST- 2013/09/10 06:00 [medline]
AID - S0301-472X(13)00061-1 [pii]
AID - 10.1016/j.exphem.2013.02.013 [doi]
PST - ppublish
SO  - Exp Hematol. 2013 Jul;41(7):604-614.e4. doi: 10.1016/j.exphem.2013.02.013. Epub 
      2013 Mar 4.