Open AccessNilotinib hampers the proliferation and function of CD8 + T lymphocytes through inhibition of T cell receptor signalling
Author(s) -
Chen J.,
Schmitt A.,
Chen B.,
Rojewski M.,
RuBeler V.,
Fei F.,
Yu Y.,
Yu X.,
Ringhoffer M.,
von Harsdorf S.,
Greiner J.,
Gbtzz M.,
Guillaume P.,
Dbhner H.,
Bunjes D.,
Schmitt M.
Publication year - 2008
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00234.x
Subject(s) - nilotinib , cytotoxic t cell , cd8 , cancer research , t cell , granzyme b , biology , antigen , immunology , imatinib , immune system , in vitro , biochemistry , myeloid leukemia
The novel selective BCR‐ABL Breakpoint cluster region – Abelson murine leukemia viral oncogene homolog 1 (BCR‐AML) inhibitor nilotinib (AMN107) is a tyrosine kinase inhibitor that is more potent against leukaemia cells in vitro than imatinib. As nilotinib might be used in the context of allogeneic stem cell transplantation where CD8 + T lymphocytes play a pivotal role in the graft‐versus‐leukaemia (GVL) effect, we investigated effects of nilotinib on this lymphocyte subpopulation. Nilotinib inhibits phytohemagglutinin (PHA)‐induced proliferation of CD8 + T lymphocytes in vitro at therapeutically relevant concentrations (0.5–4 μM). The inhibition of CD8 + T lymphocytes specific for leukaemia or viral antigens through nilotinib was associated with a reduced expansion of antigen peptide specific CD8 + T lymphocytes and with a decreased release of interferon—γ and granzyme B by these cells as analysed by flow cytometry and enzyme‐linked immunospot (ELISPOT) assays. The inhibitory effect caused by nilotinib was two times stronger than by imatinib. These effects were mediated through the inhibition of the phosphorylation of ZAP‐70, Lck and ERK 1/2 and the NF‐κβ signalling transduction pathway. Taken together, we observed a strong suppressive impact of nilotinib on the CD8 + T lymphocyte function which should be considered carefully in the framework of allogeneic stem cell transplantation or other T cell based immunotherapies.