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Published online before print March 22, 2007

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(Journal of Leukocyte Biology. 2007;81:1374-1385.)
© 2007 by Society for Leukocyte Biology

CpG oligodeoxynucleotide-enhanced humoral immune response and production of antibodies to prion protein PrP^Sc in mice immunized with 139A scrapie-associated fibrils

Daryl S. Spinner^*,1, Regina B. Kascsak^*, Giuseppe LaFauci^*, Harry C. Meeker^*, Xuemin Ye^*,2, Michael J. Flory^*, Jae Il Kim^*,3, Georgia B. Schuller-Levis^*, William R. Levis, Thomas Wisniewski, Richard I. Carp^* and Richard J. Kascsak^*,1

^* New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA; and
New York University School of Medicine, New York, New York, USA

¹ Correspondence: New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314, USA. E-mail: darylspinner{at}aol.com; rrkascsak{at}msn.com

ABSTRACT

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.

Key Words: transmissible spongiform encephalopathy (TSE) • monoclonal antibodies • innate immunity • Toll-like receptor 9 (TLR9 or TLR-9)

This article has been cited by other articles:

				D. S. Spinner, I. S. Cho, S. Y. Park, J. I. Kim, H. C. Meeker, X. Ye, G. LaFauci, D. J. Kerr, M. J. Flory, B. S. Kim, et al. Accelerated Prion Disease Pathogenesis in Toll-Like Receptor 4 Signaling-Mutant Mice J. Virol., November 1, 2008; 82(21): 10701 - 10708. [Abstract] [Full Text] [PDF]