Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection

Prion diseases are characterized by the deposition of an abnormal form (termed PrPSc) of the cellular prion protein (PrPC). Because antibodies to PrPC can antagonize deposition of PrPSc in cultured cells and mice, they may be useful for anti-prion therapy. However, induction of protective anti-prion immune responses in WT animals may be hindered by host tolerance. Here, we studied the cellular and molecular basis of tolerance to PrPC. Immunization of PrnP(o/o) mice with bacterially expressed PrP (Prp(REC)) resulted in vigorous humoral immune responses to Prp(REC) and native cell-surface PrPC. Instead, WT mice yielded antibodies that failed to recognize native PrPC despite immunoreactivity with Prp(REC), even after immunization with PrP-PrP polyprotein and/or upon administration of anti-OX40 antibodies. Consequently, immunized WT mice experienced insignificantly delayed prion pathogenesis upon peripheral prion challenge. Anti-PrP immune responses in Prnp(o/o) mice were completely abrogated by transgenic expression of PrPC in B cells, T cells, neurons, or hepatocytes, but only moderately reduced by expression in myelinating cells, despite additional thymic Prnp transcription in each case. We conclude that tolerance to PrPC can coexist with immunoreactivity to Prp(REC) and does not depend on thymic PrPC expression. Its circumvention might represent an important step toward the development of effective anti-prion immunotherapy.