NR AXLO
AU Eloit,M.; Sacquin,A.; Adam,M.; Crespeau,F.; Rosset,M.
TI Adenovirus Recombinant for MHC I-restricted PrP Epitopes Induce T CD8+ Cytotoxic Cells in Wild-type Mice: Role of CTL in Prion Disease Protection
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.181
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Background: Good evidence now exists that the anti-PrP antibodies are efficient at preventing prion disease in mice. However, no information exists on the possibility to induce CD8+ CTL in wild-type mice, and on their influence on prion diseases. In a previous work, we demonstrated that co-injection of PrP-derived MHC I-restricted nonapeptides and CpG/IFA to C57Bl/6 wt mice elicited T cells secreting IFNfx in response to the peptide, provided that they were modified to increase their binding affinity for H-2Db. Two of these peptides induced T cells cytotoxic for peptide-pulsed RMAS cells in vitro and for splenocytes loaded with the modified peptide in vivo.Yet, immunization stimulated a low frequency of peptide-specific CD8+ measured by pentamer staining.
Aim(s)/Objective(s): To improve the efficiency of CTL generation, recombinant adenovirus (rAd) were used as immunogens in C57Bl/6 wt mice to deliver PrP peptides; the capacity of these CTLs to protect against prion diseases will be evaluated in mice challenged with murine scrapie.
Methods: Based on these results, we have engineered rAds expressing minigenes encoding these modified peptides. The constructions were optimized to be independent of proteasome cleavage and of TAP transport.
Results: All wt mice immunized with one rAd developed 1 to 4% pentamer-positive CD8+ T cells the level of which remained high during the asymptomatic period without clinical signs of autoimmune reactions nor histopathological tissue destruction. These T cells were cytotoxic against PrP expressing cells and secreted specifically INFfx measured by intracellular staining.
Conclusion: This strategy proves particularly efficient in eliciting peptide-specific CD8+ CTL without inducing autoimmune reactions. Their protective capacity is under investigations in 139A-infected mice.
AD M. Eloit, M. Adam, ENVA, UMR 1161, France; A. Sacquin, M. Rosset, INSERM 712/Hopital St-Antoine, France; F. Crespeau, ENVA, Dept of histopathology, France
SP englisch
PO Schottland