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* Institute of Virology, Prion Research Group, Technical University of Munich, Munich, Germany;
Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany;
Institute of Pathology, GSF National Research Center for Environment and Health, Neuherberg, Germany;
Department of Chemistry, Institute of Biotechnology, Technical University of Munich, Munich, Germany; and
¶ Unité de Virologie et Immunologie Moléculaires, Biologie Physico-chimique des Prions, Jouy-en-Josas, France
Prion diseases are fatal neurodegenerative diseases that are characterized by the conformational conversion of the normal, mainly 
-helical cellular prion protein (PrP) into the abnormal β-sheet-rich infectious isoform (PrPSc). The immune system neither shows reaction against cellular PrP nor PrPSc, most likely due to profound self-tolerance. In previous studies, we were able to partly overcome self-tolerance using recombinantly expressed dimeric PrP (tandem PrP (tPrP)), in association with different adjuvants. Proof of principle for antiprion efficacy was obtained in vitro and in vivo. In this study, we demonstrate the induction of a specific Th1 T cell response in wild-type mice immunized with tPrP and CpG-oligonucleotide (ODN). Biochemical influences such as refolding conditions, ionic strength, pH, and interaction with CpG-ODN affected antigenic structure and thus improved immunogenicity. Furthermore, s.c. immunization with tPrP and CpG-ODN coencapsulated in biodegradable polylactide-coglycolide microspheres (PLGA-MS) enhanced CD4 T cell responses and, more prominent, the induction of CD8 T cells. In this vaccination protocol, PLGA-MS function as endosomal delivery device of Ag plus CpG-ODN to macrophages and dendritic cells. In contrast, PLGA-MS-based DNA vaccination approaches with a tPrP construct generated poor humoral and T cell responses. Our data show that prophylactic and therapeutic immunization approaches against prion infections might be feasible using tPrP Ag and CpG-ODN adjuvant without detectable side effects.
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1 This work was supported by SFB-576 (Project B12), SFB-596 (Projects A8 and B14), Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie (01KO0108), and the European Union Network of Excellence Neuroprion.
2 Address correspondence and reprint requests to Dr. Hermann M. Schätzl, Institute of Virology, Prion Research Group, Technical University of Munich, Trogerstr. 30, 81675 Munich, Germany. E-mail address: schaetzl{at}lrz.tum.de
3 Abbreviations used in this paper: CJD, Creutzfeldt-Jakob disease; AFM, atomic force microscopy; DC, dendritic cell; FTIR, Fourier transformation infrared spectroscopy; mPrP, monomeric prion protein; ODN, oligonucleotide; PLGA-MS, polylactide-coglycolide microspheres; PrP, prion protein; PrP0/0, knockout mice; PrPC, cellular PrP; PrPSc, abnormal isoformprion protein; tPrP, tandem PrP; wt, wild type; rec PrP, recombinant PrP.
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