Dendritic cell-mediated-immunization with xenogenic PrP and adenoviral vectors breaks tolerance and prolongs mice survival against experimental scrapie
2009
Bruley-Rosset , Martine (Institut National de la Santé et de la Recherche MédicaleUniversité Paris 6Assistance Publique - Hôpitaux de Paris, ParisParis(France). UMR 938Hôpital Saint-Antoine) | Sacquin , Antoine (Institut National de la Santé et de la Recherche MédicaleUniversité Paris 6Assistance Publique - Hôpitaux de Paris, ParisParis(France). UMR 938Hôpital Saint-Antoine) | Lecollinet , Sylvie (INRA , Maisons-Alfort (France). UMR 1161 Virologie) | Chaigneau , Thomas (Institut National de la Santé et de la Recherche MédicaleUniversité Paris 6Assistance Publique - Hôpitaux de Paris, ParisParis(France). UMR 938Hôpital Saint-Antoine) | Adam , Micheline (INRA , Maisons-Alfort (France). UMR 1161 Virologie) | Crespeau , François (Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort(France). Laboratoire d'Anatomopathologie) | Eloit , Marc (INRA , Maisons-Alfort (France). UMR 1161 Virologie)
In prion diseases, PrP(c), a widely expressed protein, is transformed into a pathogenic form called PrP(Sc), which is in itself infectious. Antibodies directed against PrP(c) have been shown to inhibit PrP(c) to PrP(Sc) conversion in vitro and protect in vivo from disease. Other effectors with potential to eliminate PrPSc-producing cells are cytotoxic T cells directed against PrP-derived peptides but their ability to protect or to induce deleterious autoimmune reactions is not known. The natural tolerance to PrP(c) makes difficult to raise efficient adaptive responses. To break tolerance, adenovirus (Ad) encoding human PrP (hPrP) or control Ad were administered to wild-type mice by direct injection or by transfer of Ad-transduced dendritic cells (DCs). Control Ad-transduced DCs from Tg650 mice overexpressing hPrP were also used for immunization. DC-mediated but not direct administration of AdhPrP elicited antibodies that bound to murine native PrP(c). Frequencies of PrP-specific IFN gamma-secreting T cells were low and in vivo lytic activity only targeted cells strongly expressing hPrP. Immunohistochemical analysis revealed that CD3(+) T cell infiltration was similar in the brain of vaccinated and unvaccinated 139A-infected mice suggesting the absence of autoimmune reactions. Early splenic PrP(Sc) replication was strongly inhibited ten weeks post infection and mean survival time prolonged from 209 days in untreated 139A-infected mice to 246 days in mice vaccinated with DCs expressing the hPrP. The efficacy appeared to be associated with antibody but not with cytotoxic cell-mediated PrP-specific responses.
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