title: Nilotinib hampers the proliferation and function of CD8+ T lymphocytes through inhibition of T cell receptor signalling.
abstract: 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 microM). 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-gamma 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-kappaB 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.
authors.affiliation: Third Department of Internal Medicine, University of Ulm, Ulm, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: A
authors.initials: A
authors.lastname: Schmitt
authors.forename: B
authors.initials: B
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Rojewski
authors.forename: V
authors.initials: V
authors.lastname: Rübeler
authors.forename: F
authors.initials: F
authors.lastname: Fei
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.forename: M
authors.initials: M
authors.lastname: Ringhoffer
authors.forename: S
authors.initials: S
authors.lastname: von Harsdorf
authors.forename: J
authors.initials: J
authors.lastname: Greiner
authors.forename: M
authors.initials: M
authors.lastname: Götzz
authors.forename: P
authors.initials: P
authors.lastname: Guillaume
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.forename: D
authors.initials: D
authors.lastname: Bunjes
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D011743:Pyrimidines / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C498826:nilotinib