Polylactide-coglycolide microspheres co-encapsulating recombinant tandem prion protein with CpG-oligonucleotide break self-tolerance to prion protein in wild-type mice and induce CD4 and CD8 T cell responses.
Prion diseases are fatal neurodegenerative diseases that are characterized by the conformational conversion of the normal, mainly alpha-helical cellular prion protein (PrP) into the abnormal beta-sheet-rich infectious isoform (PrP(Sc)). The immune system neither shows reaction against cellular PrP nor PrP(Sc), most likely due to profound self-tolerance. In previous studies, we were able to partly overcome self-tolerance using recombinantly expressed dimeric PrP (tandem PrP (tPrP)), in association with different adjuvants. Proof of principle for antiprion efficacy was obtained in vitro and in vivo. In this study, we demonstrate the induction of a specific Th1 T cell response in wild-type mice immunized with tPrP and CpG-oligonucleotide (ODN). Biochemical influences such as refolding conditions, ionic strength, pH, and interaction with CpG-ODN affected antigenic structure and thus improved immunogenicity. Furthermore, s.c. immunization with tPrP and CpG-ODN co-encapsulated in biodegradable polylactide-coglycolide microspheres (PLGA-MS) enhanced CD4 T cell responses and, more prominent, the induction of CD8 T cells. In this vaccination protocol, PLGA-MS function as endosomal delivery device of Ag plus CpG-ODN to macrophages and dendritic cells. In contrast, PLGA-MS-based DNA vaccination approaches with a tPrP construct generated poor humoral and T cell responses. Our data show that prophylactic and therapeutic immunization approaches against prion infections might be feasible using tPrP Ag and CpG-ODN adjuvant without detectable side effects.
Kaiser-Schulz
Gunnar
G
Institute of Virology, Prion Research Group, Technical University of Munich, Trogerstrasse 30, 81675 Munich, Germany.
Heit
Antje
A
Quintanilla-Martinez
Leticia
L
Hammerschmidt
Franziska
F
Hess
Simone
S
Jennen
Luise
L
Rezaei
Human
H
Wagner
Hermann
H
Schätzl
Hermann M
HM
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002214:Capsules / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008863:Microspheres; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D017096:Prion Diseases / Q000517:prevention & control*; D011328:Prions / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D017634:Self Tolerance; D014611:Vaccination; D019444:Vaccines, DNA / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*
D001323:Autoantibodies; C408982:CPG-oligonucleotide; D002214:Capsules; D009838:Oligodeoxyribonucleotides; D011108:Polymers; D011328:Prions; D011994:Recombinant Proteins; D019444:Vaccines, DNA; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid