Several studies have failed to demonstrate the presence of immune responses to infectious prions during the course of prion disease, reflecting the identical primary structure of normal and disease-associated isoforms and the widespread expression of the normal cellular form of prion protein, PrPC, leading to B- and/or T-cell tolerance of disease-associated isoforms and also possibly because antigen-presenting cells are unable to process the highly aggregated, detergent-insoluble, protease-resistant form, PrPSc. Under certain circumstances, PrPSc can be revealed to the immune system in immunogenic form, and it has been shown previously that anti-PrP antibodies can be induced to prions immunoadsorbed to Dynabeads using specific anti-PrP monoclonal antibodies, even in PrP-sufficient mice. This study demonstrated in a murine scrapie model that PrP–Dynabeads effectively stimulated the immune system to produce anti-PrP IgM antibodies over prolonged periods after repeated immunization. It was also shown that these immune responses prolonged incubation times in murine scrapie.
BeringueV.,
AdjouK. T.,
LamouryF.,
MaignienT.,
DeslysJ. P.,
RaceR.,
DormontD.2000; Opposite effects of dextran sulfate 500, the polyene antibiotic MS-8209, and Congo red on accumulation of the protease-resistant isoform of PrP in the spleens of mice inoculated intraperitoneally with the scrapie agent. J Virol 74:5432–5440[CrossRef]
BuelerH.,
AguzziA.,
SailerA.,
GreinerR. A.,
AutenriedP.,
AguetM.,
WeissmannC.1993; Mice devoid of PrP are resistant to scrapie. Cell 73:1339–1347[CrossRef]
EnariM.,
FlechsigE.,
WeissmannC.2001; Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc Natl Acad Sci U S A 98:9295–9299[CrossRef]
GoniF.,
PrelliF.,
SchreiberF.,
ScholtzovaH.,
ChungE.,
KascsakR.,
BrownD. R.,
SigurdssonE. M.,
ChabalgoityJ. A.,
WisniewskiT.2008; High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice. Neuroscience 153:679–686[CrossRef]
HeppnerF. L.,
MusahlC.,
ArrighiI.,
KleinM. A.,
RulickeT.,
OeschB.,
ZinkernagelR. M.,
KalinkeU.,
AguzziA.2001; Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294:178–182[CrossRef]
JonesM.,
WightD.,
McLoughlinV.,
NorrbyK.,
IronsideJ. W.,
ConnollyJ. G.,
FarquharC. F.,
MacgregorI. R.,
HeadM. W.2009; An antibody to the aggregated synthetic prion protein peptide (PrP106–126. selectively recognizes disease-associated prion protein (PrPSc) from human brain specimens. Brain Pathol (in press). doi: 10.1111/j.1750-3639.2008.00181.x
KascsakR. J.,
RubensteinR.,
MerzP. A.,
Tonna DeMasiM.,
FerskoR.,
CarpR. I.,
WisniewskiH. M.,
DiringerH.1987; Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol 61:3688–3693
KayedR.,
HeadE.,
ThompsonJ. L.,
McIntireT. M.,
MiltonS. C.,
CotmanC. W.,
GlabeC. G.2003; Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300:486–489[CrossRef]
KimberlinR. H.,
WalkerC. A.1979; Pathogenesis of scrapie: agent multiplication in brain at the first and second passage of hamster scrapie in mice. J Gen Virol 42:107–117[CrossRef]
McBrideP. A.,
EikelenboomP.,
KraalG.,
FraserH.,
BruceM. E.1992; PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice. J Pathol 168:413–418[CrossRef]
NakamuraN.,
MiyamotoK.,
ShimokawaM.,
NishidaN.,
MohriS.,
KitamotoT.,
HoriuchiH.,
FurusawaS.,
MatsudaH.2003; Generation of antibodies against prion protein by scrapie-infected cell immunization of PrP0/0 mice. Hybrid Hybridomics 22:263–266[CrossRef]
ParamithiotisE.,
PinardM.,
LawtonT.,
LaBoissiereS.,
LeathersV. L.,
ZouW. Q.,
EsteyL. A.,
LamontagneJ.,
LehtoM. T.other authors2003; A prion protein epitope selective for the pathologically misfolded conformation. Nat Med 9:893–899[CrossRef]
PeretzD.,
WilliamsonR. A.,
MatsunagaY.,
SerbanH.,
PinillaC.,
BastidasR. B.,
RozenshteynR.,
JamesT. L.,
HoughtenR. A.other authors1997; A conformational transition at the N terminus of the prion protein features in formation of the scrapie isoform. J Mol Biol 273:614–622[CrossRef]
PrusinerS. B.,
GrothD.,
SerbanA.,
KoehlerR.,
FosterD.,
TorchiaM.,
BurtonD.,
YangS.-L.,
DeArmondS. J.1993; Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. Proc Natl Acad Sci U S A 90:10608–10612[CrossRef]
SchwarzA.,
KratkeO.,
BurwinkelM.,
RiemerC.,
SchultzJ.,
HenkleinP.,
BammeT.,
BaierM.2003; Immunisation with a synthetic prion protein-derived peptide prolongs survival times of mice orally exposed to the scrapie agent. Neurosci Lett 350:187–189[CrossRef]
SigurdssonE. M.,
BrownD. R.,
DanielsM.,
KascsakR. J.,
KascsakR.,
CarpR.,
MeekerH. C.,
FrangioneB.,
WisniewskiT.2002; Immunization delays the onset of prion disease in mice. Am J Pathol 161:13–17[CrossRef]
WhiteA. R.,
EneverP.,
TayebiM.,
MushensR.,
LinehanJ.,
BrandnerS.,
AnsteeD.,
CollingeJ.,
HawkeS.2003; Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 422:80–83[CrossRef]
WilliamsonR. A.,
PeretzD.,
SmorodinskyN.,
BastidasR.,
SerbanH.,
MehlhornI.,
DeArmondS. J.,
PrusinerS. B.,
BurtonD. R.1996; Circumventing tolerance to generate autologous monoclonal antibodies to the prion protein. Proc Natl Acad Sci U S A 93:7279–7282[CrossRef]