Anti-prion activity generated by a novel vaccine formulation

Pilon, John L.; Loiacono, Christina M.; Okeson, Danelle M.; Lund, Sharon; VerCauteren, Kurt C.; Rhyan, Jack C.; Miller, Lowell A.

doi:10.1016/j.neulet.2007.10.015

Cited by 27 publications

(20 citation statements)

References 14 publications

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“…Furthermore, this report adds to the evidence that prion diseases may display an identifiable prodrome that can be clinically detected [26,27] . This may present opportunities for prophylactic therapies for individuals at risk for developing genetic prion disease [28,29] .…”

Section: Discussionmentioning

confidence: 99%

D178N, 129Val and N171S, 129Val Genotype in a Family with Creutzfeldt-Jakob Disease

Appleby

Appleby²,

Hall³

et al. 2010

Dement Geriatr Cogn Disord

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Background: Fatal familial insomnia (FFI) and genetic Creutzfeldt-Jakob disease (CJD^D178N,^129V) are two phenotypes that share a common point mutation at codon 178 of the prion protein gene (PRNP), but differ in their polymorphism at codon 129 of the mutant allele. A mutation at codon 171 of the PRNP gene has been described in a family with a strong psychiatric history without prion disease. Methods: Clinical and genetic information of a family with CJD was obtained from medical records and family informants. Results: We identified an African-American family with molecular and genetically confirmed CJD^D178N,^129V that also carried the N171S, 129V polymorphism and had a strong psychiatric clinical presentation. Conclusion: This is a complex family that carries the D178N, 129V and N171S, 129V genotype. This report is the first description of both genotypes occurring within a family with genetic human prion disease.

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Section: Discussionmentioning

confidence: 99%

D178N, 129Val and N171S, 129Val Genotype in a Family with Creutzfeldt-Jakob Disease

Appleby

Appleby²,

Hall³

et al. 2010

Dement Geriatr Cogn Disord

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“…An exciting report from White et al (2003) was the first clear evidence that passive immunization of prioninfected animals inhibits prion replication and delays development of prion disease. Following that report, a number of groups (Campana et al, 2009;Pilon et al, 2007;Song et al, 2008;Wuertzer et al, 2008) have demonstrated the effectiveness of immunization using anti-PrP antibody in delaying the onset of disease in vivo.…”

Section: Introductionmentioning

confidence: 97%

PrP-specific camel antibodies with the ability to immunodetect intracellular prion protein

Tayebi

Taylor

Jones

et al. 2010

Journal of General Virology

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Although there is currently no effective treatment for prion diseases, significant advances have been made in suppressing its progress, using antibodies that block the conversion of PrPC into PrPSc. In order to be effective in treating individuals that have prion diseases, antibodies must be capable of arresting disease in its late stages. This requires the development of antibodies with higher affinity for PrPSc and systems for effective translocation of antibodies across the blood–brain barrier in order to achieve high concentrations of inhibitor at the site of protein replication. An additional advantage is the ability of these antibodies to access the cytosol of affected cells. To this end, we have generated PrP-specific antibodies (known as PrioV) by immunization of camels with murine scrapie material adsorbed to immunomagnetic beads. The PrioV antibodies display a range of specificities with some recognizing the PrP27–30 proteinase K-resistant fragment, others specific for PrPC and a number with dual binding specificity. Independent of their PrP conformation specificity, one of the PrioV antibodies (PrioV3) was shown to bind PrPC in the cytosol of neuroblastoma cells. In marked contrast, conventional anti-PrP antibodies produced in mouse against similar target antigen were unable to cross the neuronal plasma membrane and instead formed a ring around the cells. The PrioV anti-PrP antibodies could prove to be a valuable tool for the neutralization/clearance of PrPSc in intracellular compartments of affected neurons and could potentially have wider applicability for the treatment of so-called protein-misfolding diseases.

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“…Additional boosts with 168 amplified the CD8 + T cell pool specific for the 168 native peptide and further prolonged clinical phase. The partial positive effect obtained with AdTA can be viewed as a classical adjuvant effect associated with non-specific immune stimulation and significant therapeutic benefits, as reported in two earlier studies (Tal et al, 2003;Pilon et al, 2007). However, the lack of protection following Ad217NP immunization, likely originating from peptide processing deficit, suggest that the prolongation of the clinical phase can be in part attributed to a peptide-related specific effect.…”

Section: Discussionmentioning

confidence: 60%

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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Anti-prion activity generated by a novel vaccine formulation

Cited by 27 publications

References 14 publications

D178N, 129Val and N171S, 129Val Genotype in a Family with Creutzfeldt-Jakob Disease

D178N, 129Val and N171S, 129Val Genotype in a Family with Creutzfeldt-Jakob Disease

PrP-specific camel antibodies with the ability to immunodetect intracellular prion protein

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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