Modulation of T-effector function by imatinib at the level of cytokine secretion.
OBJECTIVE
Recently, evidence was provided, that the selective tyrosine kinase inhibitor imatinib mesylate (imatinib) has immunomodulatory or suppressive effects. However, the discussion about imatinib's influence on immune cells is still controversial. The aim of this study was to clarify the effect of imatinib on CD8+ and CD4+ T-cell effector functions.


METHODS
For analyzing T-cell effector functions T-cell receptor-transgenic ovalbumin-specific CD8+ T cells and in vivo primed CD4+ Th1 cells were used. T-cell effector functions were analyzed on the level of antigen responsiveness by intracellular cytokine staining, by measuring cytokine secretion in an interferon-gamma (IFN-gamma) enzyme-linked immunosorbent assay and by detecting cytotoxicity using the fluorescein-activated cell sorting-based fluorometric assessment of T-lymphocyte antigen-specific lysis assay.


RESULTS
It was demonstrated that imatinib inhibits antigen-specific IFN-gamma secretion of both CD4+ and CD8+ T-effector cells at therapeutically relevant concentrations, while T cells remain responsive. The decrease of IFN-gamma production was not due to the loss of T-cell viability. Further, it was shown that the effector T cells are modulated rather than suppressed, because the cytolytic functions of CD8+ cytotoxic T cells were not altered. Residual cytolytic activity in the presence of imatinib was not due to FasL interaction.


CONCLUSIONS
These experiments provide evidence for a therapeutically relevant modulation of T-cell effector functions by imatinib. This might open a possible applicability of imatinib in various autoimmune and inflammatory diseases, including multiple sclerosis and rheumatoid arthritis.
Leder
Christoph
C
Department of Neurology, University of Wuerzburg, Wuerzburg, Germany.
Ortler
Sonja
S
Seggewiss
Ruth
R
Einsele
Hermann
H
Wiendl
Heinz
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D000068877:Imatinib Mesylate; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000970:Antineoplastic Agents; D001549:Benzamides; D016207:Cytokines; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate