Breaking immune tolerance to the prion protein using prion protein peptides plus oligodeoxynucleotide-CpG in mice.
The absence of a detectable immune response during transmissible spongiform encephalopathies is likely due to the fact that the essential component of infectious agents, the prion protein (PrP), is a self Ag expressed on the surface of many cells of the host. To overcome self-tolerance to PrP, we used 30-mer PrP peptides previously shown to be immunogenic in Prnp(-/-) mice, together with CFA or CpG-oligodeoxynucleotides (CpG) in IFA. Generation of anti-PrP T and B cell responses was analyzed in the spleen, lymph nodes, and serum of immunized C57BL/6 wild-type mice. Immunization with PrP peptides emulsified in CFA did not trigger an immune response to PrP. When CpG were used, vaccination with peptides P143-172 and P158-187 generated IFN-gamma-secreting splenic T cells, and only P158-187 significantly stimulated IL-4-secreting T cells. Both peptides induced few Ab-producing B cells, and low and variable serum Ab titers. In contrast, immunization with peptide P98-127 did not induce significant levels of T cell responses but elicited specific peptide Abs. T cell epitope mapping, performed using 15-mer peptides covering PrP segment 142-182, revealed that an immunogenic motif lies between positions 156 and 172. These results demonstrate that T and B cell repertoires against PrP can be stimulated in C57BL/6 when adjuvant of the innate immunity such as CpG, but not CFA, is added to PrP peptides, and that the pattern of immune responses varies according to the epitope.
Rosset
Martine Bruley
MB
Institut National de la Santé et de la Recherche Médicale and Université Pierre et Marie Curie, Hopital Saint-Antoine, Paris, France. rosset@st-antoine.inserm.fr
Ballerini
Clara
C
Gregoire
Sylvie
S
Metharom
Pat
P
Carnaud
Claude
C
Aucouturier
Pierre
P
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000595:Amino Acid Sequence; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018899:CpG Islands / Q000276:immunology; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology*; D011328:Prions / Q000008:administration & dosage* / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D011328:Prions; D015847:Interleukin-4; D007371:Interferon-gamma