期刊
BRAIN BEHAVIOR AND IMMUNITY
卷 26, 期 6, 页码 919-930出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2012.04.002
关键词
Experimental prion disease; Prion protein; CD8(+) T cells; CNS infiltration; Vaccine; Adenovirus
资金
- INSERM
- Neuroprion network of excellence
- nonprofit France Alzheimer Association
Prion diseases are caused by the transconformation of the host cellular prion protein PrPc into an infectious neurotoxic isoform called PrPSc. 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 PrPc-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-peptide; elicited a significant number of IFN gamma 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. Mini:genes 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 IFN gamma-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. (C) 2012 Elsevier Inc. All rights reserved.
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