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Open Access 01-12-2010 | Research

Effects of nilotinib on regulatory T cells: the dose matters

Authors: Fei Fei, Yingzhe Yu, Anita Schmitt, Markus T Rojewski, Baoan Chen, Jochen Greiner, Marlies Götz, Donald Bunjes, Michael Schmitt

Published in: Molecular Cancer | Issue 1/2010

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.

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Title: Effects of nilotinib on regulatory T cells: the dose matters
Authors: Fei Fei
Yingzhe Yu
Anita Schmitt
Markus T Rojewski
Baoan Chen
Jochen Greiner
Marlies Götz
Donald Bunjes
Michael Schmitt
Publication date: 01-12-2010
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-9-22

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Abstract

Background

Design and Methods

Results

Conclusions

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