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- Title
Effects of nilotinib on regulatory T cells:the dose matters.
- Authors
Fei Fei; Yingzhe Yu; Schmitt, Anita; Rojewski, Markus T.; Chen, Baoan; Greiner, Jochen; Götz, Marlies; Bunjes, Donald; Schmitt, Michael
- Abstract
Background: Nilotinib is a tyrosine kinase inhibitor with high target specificity. Here, we characterized the effects of nilotinib for the first time on CD4+CD25+ regulatory T cells (Tregs) which regulate anti-tumor/leukemia immune responses. Design and Methods: Carboxyfluorescein diacetate succinimidyl ester (CFSE) and 5-bromo-2-deoxy -uridine (BrdU) were used to assess the proliferation and cell cycle distribution of Tregs. The expression of the transcription factor forkhead box P3 (FoxP3) and the glucocorticoid-induced tumor necrosis factor receptor (GITR) were measured by flow cytometry. Western blotting analysis was used to detect the effects of nilotinib on the signal transduction cascade of T-cell receptor (TCR) in Tregs. Results: Nilotinib inhibited the proliferation and suppressive capacity of Tregs in a dose-dependent manner. However, the production of cytokines secreted by Tregs and CD4+CD25- T cells was only inhibited at high concentrations of nilotinib exceeding the mean therapeutic serum concentrations of the drug in patients. Only high doses of nilotinib arrested both Tregs and CD4+CD25- T cells in the G0/G1 phase and down-regulated the expression of FoxP3 and GITR. In western blotting analysis, nilotinib did not show significant inhibitory effects on TCR signaling events in Tregs and CD4+CD25- T cells. Conclusions: These findings indicate that nilotinib does not hamper the function of Tregs at clinical relevant doses, while long-term administration of nilotinib still needs to be investigated.
- Subjects
PROTEIN-tyrosine kinase inhibitors; DRUG dosage; T cells; CYTOKINES; IMMUNE response; CELL cycle
- Publication
Molecular Cancer, 2010, Vol 9, p22
- ISSN
1476-4598
- Publication type
Article
- DOI
10.1186/1476-4598-9-22