Nilotinib hampers the proliferation and function of CD8+ T lymphocytes through inhibition of T cell receptor signalling

• Published in: Journal of cellular and molecular medicine Vol. 12; no. 5b; pp. 2107 - 2118
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2008; John Wiley & Sons, Inc; John Wiley & Sons, Ltd
• Subjects: Abl protein; Acute myeloid leukemia; Allografts; Antibodies; Antigens; Antineoplastic Agents - pharmacology; BCR protein; Blood & organ donations; Case-Control Studies; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; chronic myeloid leukaemia; Cytomegalovirus; Dose-Response Relationship, Drug; Drug dosages; Enzyme-linked immunosorbent assay; Enzymes; Flow cytometry; functional activation; Fusion protein; Granzyme B; healthy donor; Humans; Imatinib; Immunotherapy; Kinases; Lck protein; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; lymphocyte proliferation; Lymphocyte receptors; Lymphocytes; Lymphocytes T; nilotinib; Peptides; Phosphorylation; Pyrimidines - pharmacology; Receptors, Antigen, T-Cell - drug effects; Receptors, Antigen, T-Cell - immunology; Signal transduction; Signal Transduction - drug effects; Stem cell transplantation; Stem cells; T cell receptors; Xenografts; ZAP-70 protein; Grand Island; Basel Switzerland; United States > US; Berlin Germany; Switzerland; Germany
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2008.00234.x

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.