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Published online before print February 3, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0705419

Received for publication July 28, 2005.
Revised November 16, 2005.
Accepted for publication December 8, 2005.

Article

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 Boisse ^*, Philippe Rousselot , Emmanuel Raffoux , Jean-Michel Cayuela , Jean Soulier , Nuala Mooney ^*, Dominique Charron ^*, Hervé Dombret , Antoine Toubert ^*, and Delphine Rea ^*¶@

*Laboratoire d’Immunologie et Histocompatibilité, INSERM U662, Institut Universitaire d’Hématologie, Paris, France; Service des Maladies du Sang and Laboratoire Central d’Hématologie, ^¶Unité de Thérapie Cellulaire et Clinique Transfusionnelle, AP-HP, Hôpital Saint-Louis, Paris, France; and Service d’Onco-Hématologie, Centre Hospitalier de Versailles, Le Chesnay, France

^@ To whom correspondence should be addressed. E-mail: delphine.rea{at}sls.ap-hop-paris.fr.

	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 CD14^low 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.

Key Words: CML • vaccines

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