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

Chen J, Schmitt A, Chen B, Rojewski M, Rüßeler V, Fei F, Yu Y, Yu X, Ringhoffer M, von Harsdorf S, Greiner J, Götz M, Guillaume P, Döhner H, Bunjes D, Schmitt M

Third Department of Internal Medicine, University of Ulm, 89081 Ulm, Germany.

The novel selective BCR-ABL inhibitor nilotinib (AMN107) is a tyrosine kinase inhibitor that is more potent against leukemia 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-leukemia (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 muM). The inhibition of CD8+ T lymphocytes specific for leukemia 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 analyzed 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 signaling 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.

Published 15 January 2008 in J Cell Mol Med.
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