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 PrP Sc) of the cellular prion protein ( PrP C). Because antibodies to PrP C can antagonize deposition of PrP Sc 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 PrP C. 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 PrP C. Instead, WT mice yielded antibodies that failed to recognize native PrP C 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 PrP C 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 PrP C can coexist with immunoreactivity to PrP REC and does not depend on thymic PrP C expression. Its circumvention might represent an important step toward the development of effective anti-prion immunotherapy.