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Comparative Study
. 2006 Apr;79(4):747-56.
doi: 10.1189/jlb.0705419. Epub 2006 Feb 3.

Imatinib Mesylate Minimally Affects Bcr-Abl+ and Normal Monocyte-Derived Dendritic Cells but Strongly Inhibits T Cell Expansion Despite Reciprocal Dendritic cell-T Cell Activation

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Comparative Study

Imatinib Mesylate Minimally Affects Bcr-Abl+ and Normal Monocyte-Derived Dendritic Cells but Strongly Inhibits T Cell Expansion Despite Reciprocal Dendritic cell-T Cell Activation

Nicolas Boissel et al. J Leukoc Biol. .

Abstract

In chronic myeloid leukemia, bcr-abl+ monocytes provide a unique opportunity to generate dendritic cells (DC) expressing a broad spectrum of leukemic antigens, and bcr-abl+ DC vaccines may allow immunological eradication of leukemic cells persisting under treatment with the tyrosine kinase inhibitor imatinib. However, the efficiency of bcr-abl+ DC vaccines will critically depend on the absence of deleterious effects of bcr-abl and of imatinib on DC functions. We show that bcr-abl+ monocytes, devoid of contamination of CD14low granulocytic precursors, differentiate into DC with typical immunophenotypical and functional features, and bcr-abl transcription decreases simultaneously. During differentiation, imatinib induces a slight increase of DC apoptosis and prevents CD1a up-regulation in a dose-dependent manner in bcr-abl+ and normal monocyte-derived DC, but at most, 25% of DC fail to acquire CD1a. When DC maturation is induced in the presence of imatinib, bcr-abl+ and normal monocyte-derived DC up-regulate major histocompatibility complex and costimulatory molecules, CC chemokine receptor 7 and CD83. However, secretion of interleukin-12p70 is decreased in a dose-dependent manner. Imatinib exposure of bcr-abl+ and normal monocyte-derived DC during differentiation and maturation is not detrimental to T cell immunostimulatory functions of DC. In sharp contrast, imatinib, when added to DC-T cell cultures, profoundly suppresses DC-mediated T cell proliferation, despite reciprocal DC-T cell activation attested by up-regulation of CD25 on T cells and of CD86 on DC. Our findings demonstrate that T cells, not normal or bcr-abl+ monocyte-derived DC, are major targets for imatinib immunomodulatory effects. It can be envisioned already that imatinib-free windows will be required to enable vaccination-induced, leukemia-specific T cell expansion.

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