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

Rosset, Martine Bruley; Sacquin, Antoine; Lecollinet, Sylvie; Chaigneau, Thomas; Adam, Micheline; Crespeau, François; Éloit, Marc

doi:10.1371/journal.pone.0004917

Cited by 18 publications

(16 citation statements)

References 55 publications

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“…The attack rate was reduced down to zero in mice immunized six times prior to challenge and selected for high IgA production. The advantage of using DCs as a vaccine support was also demonstrated in a recent study performed by a member of our group (Rosset et al, 2009). There, the main principle relied on the transduction of DCs from wt mice with a recombinant adenovirus coding for human PrP (hPrP), followed by administration into wt mice subsequently infected with a scrapie agent.…”

Section: Discussionmentioning

confidence: 53%

“…In the study by Rosset et al (2009), both PrP-specific cytotoxic T cells and Ab responses were analysed and circulating Abs against native mouse PrPc were significantly increased; however, the exact immune mechanisms involved were not precisely identified. Interestingly, Abs against native mouse PrP were far less efficiently generated in mice directly immunized with recombinant adenoviruses encoding hPrP, thereby underlining the advantage of targeting antigen to DCs.…”

Section: Discussionmentioning

confidence: 99%

“…The present study, in contrast with that of Rosset et al (2009), used exclusively non-transduced DCs administered immediately after differentiation/maturation and loaded with well-defined peptides. Special attention was given to understanding the role of each immunogenic constituent, i.e.…”

Section: Discussionmentioning

confidence: 99%

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

Bachy

Ballerini

Gourdain

et al. 2009

Journal of General Virology

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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. INTRODUCTIONPrion diseases, also called transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative disorders which progress slowly, induce severe neurological loss and are transmissible. The agent is most presumably the scrapie prion protein (PrP) or PrPSc, a misfolded protein, rich in beta-sheets, resulting from the transconformation of cellular PrP (PrPc). PrPc is a ubiquitous, membrane-anchored protein, which has been remarkably conserved through evolution, but whose function in health is still enigmatic. The presence of PrPSc in tissues of diseased individuals confirms the diagnosis TSE (Prusiner et al., 1998;Wisniewski et al., 1998).Prions do not spontaneously evoke antibody (Ab) or T-cell responses in diseased subjects, most likely because PrPSc, like PrPc, is not perceived as foreign or 'dangerous' (Matzinger, 1998) by the host immune system. In recent years, however, following encouraging immunotherapy results in Alzheimer's disease patients (Schenk et al., 1999), several teams have attempted to passively or actively generate adaptive immune responses against prions in wild-type (wt) mice and have shown that passive Ab treatment (Sigurdsson et al., 2003;White et al., 2003), constitutive transgenic secretion of anti-PrP IgM (Heppner et al., 2001) or active immunization using whole PrP (Sigurdsson et al., 2002), PrP peptides (Schwarz et al., 2003), PrP fragments (Bade et al., 2006) or DNA constructs encoding Prnp gene sequences (Fernandez-Borges et al., 2006) had beneficial effects on disease evolution.In order to identify major histocompatibility (MHC) class II-restricted T-cell epitopes in C57BL6 (B6)-H-2 b mice, we previously screened a bank of overlapping peptides of mouse PrP and identified two main epitopes. One is contained in peptide PrP , the other is shared by peptides PrP 143-172 and PrP . Immunization of mice made genetically deficient for PrP (Prnp 2/2 ) with PrP 97-1...

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

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

Bachy

Ballerini

Gourdain

et al. 2009

Journal of General Virology

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“…Many vaccination regimens in experimental mouse models of scrapie resulted in prolonged incubation periods, which were most often ascribed to anti-PrP antibodies (Pankiewicz et al, 2006;White et al, 2003;Peretz et al, 2001;Polymenidou et al, 2004;Bachy et al, 2010;Rosset et al, 2009). To our knowledge, our study constitutes the prime evidence that an immune manipulation can interfere with prion progression during the symptomatic period.…”

Section: Discussionmentioning

confidence: 99%

“…To date, no cure has been found for prion diseases. Recently, immunotherapeutic approaches have been developed in experimental model of neurodegenerative diseases with some success (Peretz et al, 2001;White et al, 2003;Polymenidou et al, 2004;Schenk et al, 1999;Rosset et al, 2009). PrP antibodies inhibit the conversion of PrP c to PrP Sc in vitro (Beringue et al, 2004;Pankiewick et al, 2006) and confer some degree of protection against murine scrapie in vivo (Peretz et al, 2001;White et al, 2003;Polymenidou et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice

Sacquin

Chaigneau

Defaweux

et al. 2012

Brain, Behavior, and Immunity

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a b s t r a c tPrion diseases are caused by the transconformation of the host cellular prion protein PrP c into an infectious neurotoxic isoform called PrP Sc . While vaccine-induced PrP-specific CD4 + T cells and antibodies partially protect scrapie-infected mice from disease, the potential autoreactivity of CD8 + cytotoxic T lymphocytes (CTLs) received little attention. Beneficial or pathogenic influence of PrP c -specific CTL was evaluated by stimulating a CD8 + T-cell-only response against PrP in scrapie-infected C57BL/6 mice. To circumvent immune tolerance to PrP, five PrP-derived nonamer peptides identified using prediction algorithms were anchored-optimized to improve binding affinity for H-2D b and immunogenicity (NP-peptides). All of the NP-peptides elicited a significant number of IFNc secreting CD8 + T cells that better recognized the NP-peptides than the natives; three of them induced T cells that were lytic in vivo for NP-peptide-loaded target cells. Peptides 168 and 192 were naturally processed and presented by the 1C11 neuronal cell line. Minigenes encoding immunogenic NP-peptides inserted into adenovirus (rAds) vectors enhanced the specific CD8 + T-cell responses. Immunization with rAd encoding 168NP before scrapie inoculation significantly prolonged the survival of infected mice. This effect was attributable to a significant lengthening of the symptomatic phase and was associated with enhanced CD3 + T cell recruitment to the CNS. However, immunization with Ad168NP in scrapie-incubating mice induced IFNc-secreting CD8 + T cells that were not cytolytic in vivo and did not influence disease progression nor infiltrated the brain. In conclusion, the data suggest that vaccine-induced PrP-specific CD8 + T cells interact with prions into the CNS during the clinical phase of the disease.

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Immunomodulation

Wısnıewskı

Goñi

2023

Prions and Diseases

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

Cited by 18 publications

References 55 publications

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

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

Prolongation of prion disease-associated symptomatic phase relates to CD3+ T cell recruitment into the CNS in murine scrapie-infected mice

Immunomodulation

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