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Profound Inhibition of Antigen-Specific T-Cell Effector Functions by Dasatinib

Authors' Affiliations: ¹ Immune Recovery Section, Med. Klinik und Poliklinik II, University of Würzburg, Würzburg, Germany; ² Department of Medical Biochemistry and Immunology, Cardiff University, Cardiff, United Kingdom; ³ Laboratory of Medicinal Chemistry, National Institutes of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland; and ⁴ Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

Requests for reprints: Ruth Seggewiss, Med. Klinik und Poliklinik II, University of Würzburg, C11, Room E02, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany. Phone: 49-931-201-36402; Fax: 49-931-201-36409; E-mail: Seggewiss_R{at}medizin.uni-wuerzburg.de.

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, IFN, and tumor necrosis factor ), 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.