Dasatinib inhibits recombinant viral antigen-specific murine CD4+ and CD8+ T-cell responses and NK-cell cytolytic activity in vitro and in vivo.
OBJECTIVE
Dasatinib (BMS-354825) is a small molecule Src/Abl tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Members of the Src family of kinases are involved in the induction of innate and adaptive immunity. The purpose of this study was to evaluate the inhibitory action of dasatinib on antigen-specific CD8(+) and CD4(+) T-cell function, as well as natural killer (NK) cell cytotoxicity.


METHODS
To assess dasatinib-mediated inhibition of antigen-specific T-cell proliferation, transgenic CD4(+) and CD8(+) T cells specific for ovalbumin were utilized. Endogenous CD4(+) and CD8(+) T-cell responses were determined following immunization of dasatinib-treated or control mice with a nonreplicating recombinant virus. Clearance of the RMA-S cells, a major histocompatibility complex (MHC) class I-deficient thymoma sensitive to NK-cell lysis, was analyzed in mice undergoing dasatinib treatment.


RESULTS
Dasatinib inhibited antigen-specific proliferation of murine CD4(+) and CD8(+) transgenic T cells in vitro and in vivo. Endogenous antigen-specific helper T-cell recall responses and induction of T-cell-mediated cytotoxicity following immunization with a nonreplicating recombinant virus were also inhibited. So to was the ability of NK cells to eliminate MHC class I-deficient cells in vivo.


CONCLUSIONS
These findings suggest that dasatinib has the potential to modulate the host immune response at clinical doses and highlights scope for off target applications, e.g., therapeutic immunosuppression in the context of autoimmune pathogenesis and allogeneic tissue transplantation.
Fraser
Cara K
CK
Experimental Therapeutics Laboratory, Hanson Institute, South Australia, Australia.
Blake
Stephen J
SJ
Diener
Kerrilyn R
KR
Lyons
A Bruce
AB
Brown
Michael P
MP
Hughes
Timothy P
TP
Hayball
John D
JD
D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib; D005587:Fowlpox virus / Q000235:genetics / Q000276:immunology*; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D007114:Immunization; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology*; D014161:Transduction, Genetic
D000941:Antigens; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011994:Recombinant Proteins; D013844:Thiazoles; D010047:Ovalbumin; D000069439:Dasatinib