Published online before print May 2, 2008

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(Journal of Leukocyte Biology. 2008;84:199-206.)
© 2008 by Society for Leukocyte Biology

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

Barbara Valentinis^*,1, Annalisa Capobianco, Francesca Esposito^*, Alessandro Bianchi^*, Patrizia Rovere-Querini, Angelo A. Manfredi and Catia Traversari^*

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

¹Correspondence: Molmed S.p.A., via Olgettina 58, 20132 Milan, Italy. E-mail: barbara.valentinis{at}molmed.com

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 IB-/NF-B and ERK1/2 pathways in human DCs. No activation of p38 was induced in the same experimental conditions. Our data suggest that the IB-/NF-B pathway has a critical role in the partial maturation of DCs induced by rHSP70.

Key Words: ERK1/2 • IB-/NF-B • partial maturation • humoral immunity

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