Mouse vaccination with dendritic cells loaded with prion protein peptides overcomes tolerance and delays scrapie.

Prion diseases are presumed to be caused by the accumulation in the brain of a pathological protein called prion protein (PrP) scrapie which results from the transconformation of cellular PrP, a ubiquitous glycoprotein expressed in all mammals. Since all isoforms of PrP are perceived as self by the host immune system, a major problem in designing efficient immunoprophylaxis or immunotherapy is to overcome tolerance. The present study was aimed at investigating whether bone-marrow-derived dendritic cells (DCs) loaded with peptides previously shown to be immunogenic in PrP-deficient mice, can overcome tolerance in PrP-proficient wild-type mice and protect them against scrapie. Results show that, in such mice, peptide-loaded DCs elicit both lymphokine release by T cells and antibody secretion against native cellular PrP. Repeated recalls with peptide-loaded DCs reduces the attack rate of 139A scrapie inoculated intraperitoneally and retards disease duration by 40 days. Most interestingly, survival time in individual mice appears to be correlated with the level of circulating antibody against native cellular PrP

Dendritic Cell-Mediated-Immunization with Xenogenic PrP and Adenoviral Vectors Breaks Tolerance and Prolongs Mice Survival against Experimental Scrapie

In prion diseases, PrPc, a widely expressed protein, is transformed into a pathogenic form called PrPSc, which is in itself infectious. Antibodies directed against PrPc have been shown to inhibit PrPc to PrPSc 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 PrPc 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 PrPc. Frequencies of PrP-specific IFNγ-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 PrPSc 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

Approches vaccinales des maladies neurodégénératives (applications aux maladies à prions)

Les maladies à prions sont des maladies neurodégénératives fatales causées par la transconformation d une protéine endogène, la PrPc, en une forme pathogène, la PrPsc et pour lesquelles il n existe aucune thérapie efficace. Le traitement de ces maladies par immunothérapie active se heurte à la forte tolérance à la PrPc. L objectif de ce travail a été de développer des stratégies de stimulation des réponses T CD4+ et CD8+ spécifiques de la PrPc afin d évaluer leur activité protectrice ou auto-immune chez des souris infectées par la PrPsc.La stimulation avant infection des cellules T CD4+ spécifiques des épitopes immunogènes de la PrPc a permis la production d anticorps et de cytokines ainsi que l allongement de la phase d incubation de la maladie.Les réponses T CD8+ anti-PrP pourraient éliminer des cellules accumulant la PrPSc. Nous avons caractérisé le répertoire T CD8+ et les épitopes cibles de la PrPc en utilisant différentes stratégies. L induction avant infection d une réponse T CD8+ cytotoxique spécifique d un peptide immunogène a augmenté significativement la phase clinique.Les immunisations appliquées après infection et/ou répétées ont entrainé la perte de fonction des T CD4+ et CD8+ et de l effet protecteur. La perte des réponses spécifiques est due à des T régulateurs (Tregs). De plus, ces Tregs modulent l accumulation périphérique de la PrPsc.En conclusions, en fonction du mécanisme mis en jeu par stimulation spécifique, les cellules T peuvent contrôler les différentes phases de l infection à prions sans atteintes auto-immunes délétères. Les T CD4+, CD8+ et Tregs doivent être pris en compte pour le développement d immunothérapies anti-prions efficaces.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Electrochemical removal of the picolinoyl group under mild acidic conditions. Application to the protection of amines in peptide synthesis

International audienc

ChemInform Abstract: Electrochemical Removal of the Picolinoyl Group under Mild Acidic Conditions. Application to the Protection of Amines in Peptide Synthesis.

International audienc

Traitements automatiques de l'oral et de l'écrit. Panorama des recherches et des technologies actuelles.

International audienceno abstrac

Horse behaviour and welfare

International audienceHorse behaviour and welfare is a major issue as horses are mainly sport and recreational animals where the human-animal relation is essential. Scientific studies on this topic have increased greatly over the last decade and this publication enlightens some of the major issues raised such as horse temperament, early experience, horsing and social management and equine behaviour welfare. Precise studies are described here, that are placed in the more general context of the international scientific advances.Important behavioural aspects concern: how to measure temperament traits and the genetic/experimental influences on temperament, when, how and whether to handle foals in order to improve human/foal relation, the importance of the social environment on the behaviour of young and adult horses. On the other hand, the improvement of equine welfare through better practices is described such as housing design, feeding practices or social grouping. The use of behavioural cues in order to assess welfare is discussed and tested through experimental approaches.This book constitutes a very rich overview of the recent and new research lines in the field of horse behaviour and welfare

Fourth International Workshop on Spoken Dialog Systems

These proceedings presents the state-of-the-art in spoken dialog systems with applications in robotics, knowledge access and communication. It addresses specifically: 1. Dialog for interacting with smartphones; 2. Dialog for Open Domain knowledge access; 3. Dialog for robot interaction; 4. Mediated dialog (including crosslingual dialog involving Speech Translation); and, 5. Dialog quality evaluation. These articles were presented at the IWSDS 2012 workshop