DNA vaccination can break immunological tolerance to PrP in wild-type mice and attenuates prion disease after intracerebral challenge

被引:36
作者
Fernandez-Borges, Natalia
Brun, Alejandro
Whitton, J. Lindsay
Parra, Beatriz
Diaz-San Segundo, Fayna
Salguero, Francisco J.
Torres, Juan M.
Rodriguez, Fernando
机构
[1] Edifici CReSA, Barcelona 08193, Spain
[2] INIA, CISA, Madrid 28130, Spain
[3] Scripps Res Inst, Dept Mol & Integrat Neurosci, La Jolla, CA 92037 USA
关键词
D O I
10.1128/JVI.01210-06
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Transmissible spongiform encephalopathies (TSEs) can be ameliorated by prion protein (PrP)-specific antibodies, but active immunization is complicated by immune tolerance to the normal cellular host protein (PrPC). Here, we show that DNA immunization of wild-type mice can break immune tolerance against the prion protein, resulting in the induction of PrP-specific antibody and T-cell responses. PrP immunogenicity was increased by fusion to the lysosomal targeting signal from LIMPII (lysosomal integral membrane protein type II). Although mice immunized with a PrP-LIMPII DNA vaccine showed a dramatic delay in the onset of early disease signs after intracerebral challenge, immunization against PrP also had some deleterious effects. These results clearly confirm the feasibility of using active immunization to protect against TSEs and, in the absence of effective treatments, indicate a suitable alternative for combating the spread of these diseases.
引用
收藏
页码:9970 / 9976
页数:7
相关论文
共 29 条
[1]   Doctors seek lost data on Alzheimer's vaccine [J].
Abbott, A .
NATURE, 2004, 430 (7001) :715-715
[2]   Antiprion immunotherapy: To suppress or to stimulate? [J].
Aguzzi, A ;
Sigurdson, CJ .
NATURE REVIEWS IMMUNOLOGY, 2004, 4 (09) :725-736
[3]   Targeting antigen in mature dendritic cells for simultaneous stimulation of CD4+ and CD8+ T cells [J].
Bonini, C ;
Lee, SP ;
Riddell, SR ;
Greenberg, PD .
JOURNAL OF IMMUNOLOGY, 2001, 166 (08) :5250-5257
[4]   In vitro generation of infectious scrapie prions [J].
Castilla, J ;
Saá, P ;
Hetz, C ;
Soto, C .
CELL, 2005, 121 (02) :195-206
[5]   Early detection of PRPres in BSE-infected bovine PrP transgenic mice [J].
Castilla, J ;
Adán, AG ;
Brun, A ;
Pintado, B ;
Ramírez, MA ;
Parra, B ;
Doyle, D ;
Rogers, M ;
Salguero, FJ ;
Sánchez, C ;
Sánchez-Vizcaíno, JM ;
Torres, JM .
ARCHIVES OF VIROLOGY, 2003, 148 (04) :677-691
[6]   DNA vaccination breaks tolerance for a neo-self antigen in liver: A transgenic murine model of autoimmune hepatitis [J].
Djilali-Saiah, I ;
Lapierre, P ;
Vittozi, S ;
Alvarez, F .
JOURNAL OF IMMUNOLOGY, 2002, 169 (09) :4889-4896
[7]   Mucosal vaccination delays or prevents prion infection via an oral route [J].
Goñi, F ;
Knudsen, E ;
Schreiber, F ;
Scholtzova, H ;
Pankiewicz, J ;
Carp, R ;
Meeker, HC ;
Rubenstein, R ;
Brown, DR ;
Sy, MS ;
Chabalgoity, JA ;
Sigurdsson, EM ;
Wisniewski, T .
NEUROSCIENCE, 2005, 133 (02) :413-421
[8]   Recent developments in prion immunotherapy [J].
Heppner, FL ;
Aguzzi, A .
CURRENT OPINION IN IMMUNOLOGY, 2004, 16 (05) :594-598
[9]   Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies [J].
Heppner, FL ;
Musahl, C ;
Arrighi, I ;
Klein, MA ;
Rülicke, T ;
Oesch, B ;
Zinkernagel, RM ;
Kalinke, U ;
Aguzzi, A .
SCIENCE, 2001, 294 (5540) :178-182
[10]   Generation of monoclonal antibodies against human prion proteins in PrP0/0 mice [J].
Krasemann, S ;
Groschup, MH ;
Harmeyer, S ;
Hunsmann, G ;
Bodemer, W .
MOLECULAR MEDICINE, 1996, 2 (06) :725-734