Polyclonal anti-PrP auto-antibodies induced with dimeric PrP interfere efficiently with PrPSc propagation in prion-infected cells.
Prion diseases are neurodegenerative infectious disorders for which no prophylactic regimens are known. In order to induce antibodies/auto-antibodies directed against surface-located PrP(c), we used a covalently linked dimer of mouse prion protein expressed recombinantly in Escherichia coli. Employing dimeric PrP as an immunogen we were able to effectively overcome autotolerance against murine PrP in PrP wild-type mice without inducing obvious side effects. Treatment of prion-infected mouse cells with polyclonal anti-PrP antibodies generated in rabbit or auto-antibodies produced in mice significantly inhibited endogenous PrP(Sc) synthesis. We show that polyclonal antibodies are binding to surface-located PrP(c), thereby interfering with prion biogenesis. This effect is much more pronounced in the presence of full IgG molecules, which, unlike Fab fragments, seem to induce a significant cross-linking of surface PrP. In addition, we found immune responses against different epitopes when comparing antibodies induced in rabbits and PrP wild-type mice. Only in the auto-antibody situation in mice an immune reaction against a region of PrP is found that was reported to be involved in the PrP(Sc) conversion process. Our data point to the possibility of developing means for an active immunoprophylaxis against prion diseases.
Gilch
Sabine
S
Gene Center Munich, Max von Pettenkofer-Institute for Virology, Ludwig-Maximilians-University of Munich, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany.
Wopfner
Franziska
F
Renner-Müller
Ingrid
I
Kremmer
Elisabeth
E
Bauer
Christine
C
Wolf
Eckhard
E
Brem
Gottfried
G
Groschup
Martin H
MH
Schätzl
Hermann M
HM
D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D000939:Epitopes; D004926:Escherichia coli / Q000378:metabolism; D005260:Female; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011233:Precipitin Tests; D011328:Prions / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
D000939:Epitopes; D007074:Immunoglobulin G; D011328:Prions; D011994:Recombinant Proteins