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Profound inhibition of antigen-specific T-cell effector functions by dasatinib.
Weichsel, Ralf; Dix, Carolin; Wooldridge, Linda; Clement, Matthew; Fenton-May, Angharad; Sewell, Andrew K; Zezula, Josef; Greiner, Elisabeth; Gostick, Emma; Price, David A; Einsele, Hermann; Seggewiss, Ruth.
Afiliação
  • Weichsel R; Immune Recovery Section, Med. Klinik und Poliklinik II, University of Würzburg, Würzburg, Germany.
Clin Cancer Res ; 14(8): 2484-91, 2008 Apr 15.
Article em En | MEDLINE | ID: mdl-18413841
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, IFN gamma, and tumor necrosis factor alpha), 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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Tiazóis / Linfócitos T / Inibidores de Proteínas Quinases Limite: Humans Idioma: En Revista: Clin Cancer Res Assunto da revista: NEOPLASIAS Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Tiazóis / Linfócitos T / Inibidores de Proteínas Quinases Limite: Humans Idioma: En Revista: Clin Cancer Res Assunto da revista: NEOPLASIAS Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Alemanha