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Contribution of Antibody and T Cell-Specific Responses to the Progression of 139A-Scrapie in C57BL/6 Mice Immunized with Prion Protein Peptides¹

Antoine Sacquin^*, Anne Sophie Bergot, Pierre Aucouturier^* and Martine Bruley-Rosset^2,*

^* Institut National de la Santé et de la Recherche Médicale UMRS 893, Paris; Université Pierre et Marie Curie Univ Paris 06, Hôpital Saint-Antoine, Paris, France; and Centre National de la Recherche Scientifique/Unité Mixte de Recherche; Université Pierre et Marie Curie Univ Paris 06, Hôpital La Pitié Salpetrière, Paris, France

Prion diseases are associated with the conversion of the normal host cellular prion protein to an abnormal protease-resistant (PrPres) associated with infectivity. No specific immune response against prions develops during infection due to the strong tolerance to cellular prion protein. We examined the protective potential on prion diseases of immune responses elicited in C57BL/6 mice with PrP peptides 98–127 (P5) or 158–187 (P9) with CpG. After immunization, P5-treated mice developed high titer and long-lasting Abs, and P9-treated mice developed transient IFN- secreting T cells and poor and variable Ab responses. Both treatments impaired early accumulation of PrPres in the spleen and prolonged survival of mice infected with 139A scrapie. Additional P9 boosts after 139A infection sustained the T cell response and partially inhibited PrPres early accumulation but did not improve the survival. Surprisingly, when P9 injections were started 1 mo after infection and repeated subsequently, specific T cell and Ab responses were impaired and no beneficial effect on prion disease was observed. After a single injection of P9, the number of IFN- secreting CD4⁺ T cells was also reduced in mice 8- to 10-wk postinfection compared with healthy mice. In vivo and in vitro removal of CD4⁺CD25⁺ T cells restored the T cell response to P9 in infected mice. In conclusion, CD4⁺ T cells as well as Abs might participate to the protection against scrapie. Of importance, the peripheral accumulation of PrPres during infection negatively interferes with the development of T and B cell responses to PrP and regulatory T cells might contribute to this phenomenon.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from Institut National de la Santé et de la Recherche Médicale and the Neuroprion network of excellence, European FP6.

² Address correspondence and reprint requests to Dr. Martine Bruley Rosset, Institut National de la Santé et de la Recherche Médicale UMR 893, Bâtiment Kourilsky, Hôpital Saint-Antoine, 184 rue du faubourg Saint Antoine, F-75571 Paris Cedex 12, France. E-mail address: rosset{at}st-antoine.inserm.fr

³ Abbreviations used in this paper: PrPc, cellular prion protein; DC, dendritic cell; PrPSc, scrapie PrP; PrPres, resistant PrP; p.i., postinfection; Treg, regulatory T cell; wt, wild type; PK, proteinase K.