DNA vaccination can break immunological tolerance to PrP in wild-type mice and attenuates prion disease after intracerebral challenge.
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 (PrP(C)). 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.
Fernandez-Borges
Natalia
N
Edifici Centre de Recerca en Sanitat Animal, Campus de la UAB, Bellaterra, Cerdanyola del Valles, Barcelona 08193, Spain. Fernando.Rodriguez@cresa.uab.es
Brun
Alejandro
A
Whitton
J Lindsay
JL
Parra
Beatriz
B
Diaz-San Segundo
Fayna
F
Salguero
Francisco J
FJ
Torres
Juan M
JM
Rodriguez
Fernando
F
D000818:Animals; D000906:Antibodies / Q000097:blood; D018955:CD36 Antigens / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000096:biosynthesis; D016131:Lymphocyte Subsets; D051907:Lysosomal Membrane Proteins / Q000235:genetics; D051379:Mice; D018621:PrPC Proteins / Q000276:immunology*; D018620:PrPSc Proteins / Q000276:immunology*; D017096:Prion Diseases / Q000276:immunology* / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology*
D000906:Antibodies; D018955:CD36 Antigens; D051907:Lysosomal Membrane Proteins; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011993:Recombinant Fusion Proteins; C489452:Scarb2 protein, mouse; D019444:Vaccines, DNA; D007371:Interferon-gamma