Contribution of Antibody and T Cell-Specific Responses to the Progression of 139A-Scrapie in C57BL/6 Mice Immunized with Prion Protein Peptides

Sacquin, Antoine; Bergot, Anne‐Sophie; Aucouturier, Pièrre; Bruley-Rosset, M.

doi:10.4049/jimmunol.181.1.768

Cited by 11 publications

(11 citation statements)

References 48 publications

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“…infection and extended survival by 16 days compared with controls. Active immunization with PrP 98-127 or PrP 158-187 in the presence of CpG induced T cells and Ab production but prolonged mouse survival by only 20 days (Sacquin et al, 2008). More encouraging results have been obtained by Goni et al (2008) following oral immunization with Salmonella typhimurium encoding one or two copies of mouse Prnp in their genome.…”

Section: Discussionsupporting

confidence: 50%

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: Discussionsupporting

confidence: 50%

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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“…Tregs are probably not imported within the cohort of T cells that comes from PrP-deficient donors, but they may develop in PrP-sufficient hosts and may affect nonboosted T cells more heavily than regularly challenged T cells. A recent study from our laboratory demonstrated the development of such regulatory T cells, notably when mice were infected with 139A (55).…”

Section: Discussionmentioning

confidence: 99%

“…Ab against PrPc was measured using a previously described immunofluorescence assay on transfected EL4 cells overexpressing PrPc (50,55). Fig.…”

Section: Absence Of Significant Ab Response In Recipients Of Primed Lmentioning

confidence: 99%

“…Ab binding to native PrPc was measured by indirect immunofluorescence, as described previously (45,50,55), on a stably transfected EL4 T cell clone activated overnight with anti-CD3 Ab (clone 2C11 at 10 g/ml) to maximize cell surface PrPc. Cells, blocked first for Fc receptors, were incubated for 20 min with serum dilutions at 1/10, 1/50, and 1/100, washed in FACS buffer, and revealed for 20 min with clone Mark1, a FITC-conjugated rat anti-mouse -chain Ab.…”

Section: Detection Of Abs Against Native Prpcmentioning

confidence: 99%

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Adoptive Transfer of T Lymphocytes Sensitized against the Prion Protein Attenuates Prion Invasion in Scrapie-Infected Mice

Gourdain

Grégoire

Iken

et al. 2009

The Journal of Immunology

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There is to date no effective way of preventing or curing neurodegenerative diseases such as Alzheimer disease or transmissible spongiform encephalopathies. The idea of treating those conditions by immunological approaches has progressively emerged over the last ten years. Encouraging results have been reported in Alzheimer disease and in peripheral forms of mouse prion diseases following passive injection of Abs or active immunization against the peptides or proteins presumably at the origin of those disorders. Still, major difficulties persist due to some characteristics of those conditions such as slow evolution, brain location, uncertainties regarding precise pathogenic pathways, and, above all, the fact that the target Ag is self, meaning that it is poorly immunogenic and potentially harmful if tolerance was transgressed. To analyze some of those difficulties, we are developing adoptive cell transfer approaches. In this study, lymphocytes sensitized against the prion protein in nontolerant Prnp−/− mice were transferred into histocompatible wild-type recipients which were partly or totally devoid of their own lymphocytes. Under such conditions, we found that the engrafted T lymphocytes resisted peripheral tolerance, remained reactive for several months against epitopes of the prion protein, and significantly attenuated the progression of prions in secondary lymphoid organs with subsequent delay in the evolution of the neurological disease. Interestingly, those protective T lymphocytes secreted lymphokines and migrated more readily into the host CNS but did not appear to be engaged in cooperation with host B cells for Ab production.

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“…The same Ad168NP immunization procedure performed with 139A-incubating mice is not associated with an extended clinical phase. We showed previously that PrP 158-197 -specific CD4 + T cell responses were blunted when immunization was performed in 139A-incubating mice (Sacquin et al, 2008). In vivo and in vitro depletion of CD4 + CD25 + T cells completely restores the in vitro T-cell response to PrP , suggesting the development of an immune regulatory mechanism during prion accumulation.…”

Section: Discussionmentioning

confidence: 83%

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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Contribution of Antibody and T Cell-Specific Responses to the Progression of 139A-Scrapie in C57BL/6 Mice Immunized with Prion Protein Peptides

Cited by 11 publications

References 48 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

Adoptive Transfer of T Lymphocytes Sensitized against the Prion Protein Attenuates Prion Invasion in Scrapie-Infected Mice

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

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