Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Published online before print May 2, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0807548

Received for publication August 16, 2007.
Revised March 10, 2008.
Accepted for publication March 26, 2008.

Article

Human recombinant heat shock protein 70 affects the maturation pathways of dendritic cells in vitro and has an in vivo adjuvant activity

Barbara Valentinis *@, Annalisa Capobianco {dagger}, Francesca Esposito *, Alessandro Bianchi *, Patrizia Rovere-Querini {dagger}, Angelo A. Manfredi {dagger}, and Catia Traversari *

*Molmed S.p.A., Milan, Italy; and {dagger}Cancer Immunotherapy & Gene Therapy Program, H. San Raffaele Scientific Institute and Università Vita-Salute, Milano, Italy

@ To whom correspondence should be addressed. E-mail: barbara.valentinis{at}molmed.com.


  Abstract

Heat shock proteins (HSPs) are potent inducers of an antigen-specific immunological response. A role of chaperon of immunogenic peptides and a direct effect on APC activation and function have been described. However, the signal transduction events involved in the activation of human APCs are poorly characterized. We investigated, using human monocyte-derived dendritic cells (DCs), the signal transduction pathways activated by a human recombinant HSP70 (r)HSP70 purified from eukaryotic cells. rHSP70 effectively induced a partial maturation of DCs in vitro and a significant increase in the titers of antigen-specific IgG when used as a vaccine adjuvant in vivo. rHSP70 did not desensitize human DCs to LPS stimulation and retained its adjuvant properties in C3H/HeJ mice, which are LPS-resistant as a result of a mutation in TLR-4, ruling out the potential interference of LPS contamination. Effects on DC maturation and in vivo functions correlate to the ability of rHSP70 to activate I{kappa}B-{alpha}/NF-{kappa}B and ERK1/2 pathways in human DCs. No activation of p38 was induced in the same experimental conditions. Our data suggest that the I{kappa}B-{alpha}/NF-{kappa}B pathway has a critical role in the partial maturation of DCs.

Key Words: ERK1/2 • I{kappa}B-{alpha}/NF-{kappa}B • partial maturation • humoral immunity






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Copyright © 2008 by the Society for Leukocyte Biology.