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Profound inhibition of antigen-specific T-cell effector functions by dasatinib

Weichsel, Ralf, Dix, Carolin, Wooldridge, Linda, Clement, Mathew, Fenton-May, Angharad, Sewell, Andrew K., Zezula, Josef, Greiner, Elizabeth, Gostick, Emma, Price, David, Einsele, Hermann and Seggewiss, Ruth 2008. Profound inhibition of antigen-specific T-cell effector functions by dasatinib. Clinical Cancer Research 14 (8) , pp. 2484-2491. 10.1158/1078-0432.CCR-07-4393

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Abstract

Purpose: The dual BCR-ABL/SRC kinase inhibitor dasatinib entered the clinic for the treatment of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Because SRC kinases are known to play an important role in physiologic T-cell activation, we analyzed the immunobiological effects of dasatinib on T-cell function. The effect of dasatinib on multiple T-cell effector functions was examined at clinically relevant doses (1-100 nmol/L); the promiscuous tyrosine kinase inhibitor staurosporine was used as a comparator. Experimental Design: Purified human CD3+ cells and virus-specific CD8+ T cells from healthy blood donors were studied directly ex vivo; antigen-specific effects were confirmed in defined T-cell clones. Functional outcomes included cytokine production (interleukin-2, IFNγ, and tumor necrosis factor α), degranulation (CD107a/b mobilization), activation (CD69 up-regulation), proliferation (carboxyfluorescein diacetate succinimidyl ester dilution), apoptosis/necrosis induction, and signal transduction. Results: Both dasatinib and staurosporine inhibited T-cell activation, proliferation, cytokine production, and degranulation in a dose-dependent manner. Mechanistically, this was mediated by the blockade of early signal transduction events and was not due to loss of T-cell viability. Overall, CD4+ T cells seemed to be more sensitive to these effects than CD8+ T cells, and naïve T cells more sensitive than memory T-cell subsets. The inhibitory effects of dasatinib were so profound that all T-cell effector functions were shut down at therapeutically relevant concentrations. Conclusion: These findings indicate that caution is warranted with use of this drug in the clinical setting and provide a rationale to explore the potential of dasatinib as an immunosuppressant in the fields of transplantation and T-cell–driven autoimmune diseases

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Uncontrolled Keywords: Dasatinib ; T lymphocyte subsets ; Cytomegalovirus ; EBV
ISSN: 1078-0432
Last Modified: 02 Jan 2018 21:28
URI: http://orca.cf.ac.uk/id/eprint/6164

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