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CpG oligodeoxynucleotide‐enhanced humoral immune response and production of antibodies to prion protein PrP Sc in mice immunized with 139A scrapie‐associated fibrils
Author(s) -
Spinner Daryl S.,
Kascsak Regina B.,
LaFauci Giuseppe,
Meeker Harry C.,
Ye Xuemin,
Flory Michael J.,
Kim Jae Il,
SchullerLevis Georgia B.,
Levis William R.,
Wisniewski Thomas,
Carp Richard I.,
Kascsak Richard J.
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1106665
Subject(s) - scrapie , biology , prnp , epitope , immune system , antibody , virology , humoral immunity , immunology , gene , biochemistry , prion protein , medicine , allele , disease , pathology
Prion diseases are characterized by conversion of the cellular prion protein (PrP C ) to a protease‐resistant conformer, the srapie form of PrP (PrP Sc ). Humoral immune responses to nondenatured forms of PrP Sc have never been fully characterized. We investigated whether production of antibodies to PrP Sc could occur in PrP null (Prnp −/− ) mice and further, whether innate immune stimulation with the TLR9 agonist CpG oligodeoxynucleotide (ODN) 1826 could enhance this process. Whether such stimulation could raise anti‐PrP Sc antibody levels in wild‐type (Prnp +/+ ) mice was also investigated. Prnp −/− and Prnp +/+ mice were immunized with nondenatured 139A scrapie‐associated fibrils (SAF), with or without ODN 1826, and were tested for titers of PrP‐specific antibodies. In Prnp −/− mice, inclusion of ODN 1826 in the immunization regime increased anti‐PrP titers more than 13‐fold after two immunizations and induced, among others, antibodies to an N‐terminal epitope, which were only present in the immune repertoire of mice receiving ODN 1826. mAb 6D11, derived from such a mouse, reacts with the N‐terminal epitope QWNK in native and denatured forms of PrP Sc and recombinant PrP and exhibits a K d in the 10 − 11 M range. In Prnp +/+ mice, ODN 1826 increased anti‐PrP levels as much as 84% after a single immunization. Thus, ODN 1826 potentiates adaptive immune responses to PrP Sc in 139A SAF‐immunized mice. These results represent the first characterization of humoral immune responses to nondenatured, infectious PrP Sc and suggest methods for optimizing the generation of mAbs to PrP Sc , many of which could be used for diagnosis and treatment of prion diseases.