title: Vaccines targeting self-antigens: mechanisms and efficacy-determining parameters.
abstract: We recently showed that it is possible to compromise tumor vessel function and, as a consequence, suppress growth of aggressive preclinical tumors by immunizing against the tumor vascular markers extra domain-A (ED-A) or -B (ED-B) of fibronectin, using a fusion protein consisting of the ED-A or ED-B peptide fused to bacterial thioredoxin. To address the mechanism behind fusion protein-induced immunization and the specific contribution of the different vaccine constituents to elicit an anti-self-antibody response, we immunized mice with modified or unmodified self-antigens, combined with different adjuvant components, and analyzed antibody responses by ELISA in sera. Several essential requirements to circumvent tolerance were identified: (1) a potent pattern recognition receptor agonist like an oligonucleotide containing unmethylated cytosine and guanine dinucleotides (CpG); (2) a depot adjuvant to keep the CpG at the site of injection; and (3) the presence of foreign sequences in the vaccine protein. Lack of either of these factors abolished the anti-self-response (P = 0.008). In mice genetically deficient for type I IFN signaling, there was a 60% reduction in the anti-self-response compared with wild-type (P = 0.011), demonstrating a key role of this pathway in CpG-induced circumvention of self-tolerance. Identification of these mechanistic requirements to generate a potent anti-self-immune response should significantly aid the design of efficient, specific, and safe therapeutic cancer vaccines.
authors: *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors: Falk
authors: F
authors: Saupe
authors: *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors: Elisabeth J M
authors: EJ
authors: Huijbers
authors: *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors: Tobias
authors: T
authors: Hein
authors: *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors: Julia
authors: J
authors: Femel
authors: *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors: Jessica
authors: J
authors: Cedervall
authors: *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Uppsala, Sweden anna-karin.olsson@imbim.uu.se.
authors: Anna-Karin
authors: AK
authors: Olsson
authors: *Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, and Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, Uppsala, Sweden.
authors: Lars
authors: L
authors: Hellman
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D018899:CpG Islands / Q000276:immunology; D005260:Female; D005353:Fibronectins / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D001324:Autoantigens; D019496:Cancer Vaccines; D005353:Fibronectins; D007370:Interferon Type I
keywords: CpG; ED-B of fibronectin; adjuvant,; cancer; type I IFN