Colloquium PaperTherapeutic Vaccines: Realities of Today and Hopes for Tomorrow: Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection

摘要

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.