NR AXOX
AU Iken,S.; Chebaro,Y.; Rosset,M.B.; Derreumaux,P.; Aucouturier,P.
TI Therapeutic Vaccines Based on Chimeric Conformational Peptides : Can We Protect from Scrapie without Breaking T-cell Tolerance?
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.17
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Background: Immunotherapeutic approaches in TSE face several pitfalls, most of which relate to a strong natural tolerance of the adaptive immune system. Experiments in the mouse revealed that peripheral T cells directed to identified MHC class II epitopes exist but are anergic, and that the B-cell primary repertoire is hardly permissive for efficient antibody responses to PrPc epitopes. Breaking CD4+ T-cell tolerance to PrP proves possible, but uncontroled effector responses may induce deletorious autoimmune reactions.
Aim(s)/Objective(s): A promising alternative strategy is to design immunogens that could evoke humoral responses directed to cryptic PrP epitopes only accessible on PrPsc isoforms, by forcing B-cell cooperation with helper T-cells directed to exogenous (non-PrP) peptides.
Methods: Analyses on two distinct proposed PrPsc structural models termed 'betahelix' (Govaerts et al., 2004) and 'spiral' (DeMarco et al., 2006) allowed us to identify epitopes buried in physiological PrPc and likely to be specifically exposed on scrapieassociated isoforms. Chimeric peptides coupling the potential PrPsc B-cell epitopes with MHC II (IA-b) exogenous epitopes were designed using ab initio simulations (Derreumaux, 2000) with the requirement that the B-cell epitopes remain accessible to solvent. Specificity and intensity of antibody responses in immunised mice were analysed by ELISA and cytofluorimetric methods.
Results: We will present results from a series of vaccination experiments in 139A infected C57BL/6 mice with different combinations of PrP peptide segments, helper Tcell epitopes and adjuvants. Two overlapping 8-mer and 9-mer peptides located between helices H1 and H2 of the PrPc structure were conjugated to two different exogenous IA-b restricted epitopes.
Conclusion: In comparison with published trials, this structure-based, in silico strategy proves particularly efficient, even when applied more than 10 weeks after scrapie inoculation to mice. Conclusions will be proposed on how to optimise active immunotherapeutic treatments using conformational PrPsc epitopes.
AD S. Iken, M. Rosset, P. Aucouturier, Inserm and University Pierre & Marie Curie, UMR S712, France; Y. Chebaro, P. Derreumaux, IBPC, CNRS & Université Denis Diderot, UPR 9080, France
SP englisch
PO Schottland