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* Área de Hepatología y Terapia Génica, Universidad de Navarra, Centro de Investigación Médica Aplicada, Pamplona, Spain;
Institut Pasteur, Unité de Régulation Immunitaire et Vaccinologie, Paris, France; and
Institut National de la Santé et de la Recherche Médicale E352, Paris, France
Vaccination strategies based on the in vivo targeting of Ags to dendritic cells (DCs) are needed to improve the induction of specific T cell immunity against tumors and infectious agents. In this study, we have used a recombinant protein encompassing the extra domain A from fibronectin (EDA), an endogenous ligand for TLR4, to deliver Ags to TLR4-expressing DC. The purified EDA protein was shown to bind to TLR4-expressing HEK293 cells and to activate the TLR4 signaling pathway. EDA also stimulated the production by DC of proinflammatory cytokines such as IL-12 or TNF-
and induced their maturation in vitro and in vivo. A fusion protein between EDA and a cytotoxic T cell epitope from OVA efficiently presented this epitope to specific T cells and induced the in vivo activation of a strong and specific CTL response. Moreover, a fusion protein containing EDA and the full OVA also improved OVA presentation by DC and induced CTL responses in vivo. These EDA recombinant proteins protected mice from a challenge with tumor cells expressing OVA. These results strongly suggest that the fibronectin extra domain A may serve as a suitable Ag carrier for the development of antiviral or antitumoral vaccines.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Gobierno de Navarra Lasarte (to J.J.), Instituto de Salud Carlos III (C03/02), and the Unión Temporal de Empresas-Centro de Investigación Médica Aplicada project.
2 Address correspondence and reprint requests to Dr. Juan José Lasarte, Área de Hepatología y Terapia Génica, Universidad de Navarra, Centro de Investigación Médica Aplicada, Avenida Pío XII 55, 31008 Pamplona, Spain. E-mail address: jjlasarte{at}unav.es
3 Abbreviations used in this paper: DC, dendritic cell; EDA, extra domain A from fibronectin; BM, bone marrow; BMDC, BM-derived DC; CM, conditioned medium; ELAM, endothelial leukocyte adhesion molecule; Hsp, heat shock protein; hTLR4, human TLR4; KO, knockout; PAMP, pathogen-associated molecular pattern; SEAP, secreted embryonic alkaline phosphatase; WT, wild type.
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