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Mol Cancer. 2010 Jan 29;9:22. doi: 10.1186/1476-4598-9-22.

Effects of nilotinib on regulatory T cells: the dose matters.

Author information

1
Department of Internal Medicine III, University of Ulm, 89081 Ulm, Germany.

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.

PMID:
20113470
PMCID:
PMC2835656
DOI:
10.1186/1476-4598-9-22
[Indexed for MEDLINE]
Free PMC Article

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