title: Immunochemical termination of self-tolerance.
abstract: The ability to selectively induce a strong immune response against self-proteins, or increase the immunogenicity of specific epitopes in foreign antigens, would have a significant impact on the production of vaccines for cancer, protein-misfolding diseases, and infectious diseases. Here, we show that site-specific incorporation of an immunogenic unnatural amino acid into a protein of interest produces high-titer antibodies that cross-react with WT protein. Specifically, mutation of a single tyrosine residue (Tyr(86)) of murine tumor necrosis factor-alpha (mTNF-alpha) to p-nitrophenylalanine (pNO(2)Phe) induced a high-titer antibody response in mice, whereas no significant antibody response was observed for a Tyr(86) --> Phe mutant. The antibodies generated against the pNO(2)Phe are highly cross-reactive with native mTNF-alpha and protect mice against lipopolysaccharide (LPS)-induced death. This approach may provide a general method for inducing an antibody response to specific epitopes of self- and foreign antigens that lead to a neutralizing immune response.
authors.affiliation: Department of Chemistry, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Grünewald
authors.forename: Meng-Lin
authors.initials: ML
authors.lastname: Tsao
authors.forename: Roshan
authors.initials: R
authors.lastname: Perera
authors.forename: Liqun
authors.initials: L
authors.lastname: Dong
authors.forename: Frank
authors.initials: F
authors.lastname: Niessen
authors.forename: Ben G
authors.initials: BG
authors.lastname: Wen
authors.forename: Diane M
authors.initials: DM
authors.lastname: Kubitz
authors.forename: Vaughn V
authors.initials: VV
authors.lastname: Smider
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ruf
authors.forename: Marc
authors.initials: M
authors.lastname: Nasoff
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lerner
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D003141:Communicable Diseases / Q000235:genetics / Q000276:immunology; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D007120:Immunochemistry; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics / Q000276:immunology; D051379:Mice; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics / Q000276:immunology; D009596:Nitrophenols / Q000276:immunology / Q000494:pharmacology; D017634:Self Tolerance / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D014612:Vaccines / Q000235:genetics / Q000276:immunology
chemical_list: D000939:Epitopes; D008070:Lipopolysaccharides; D009596:Nitrophenols; D014409:Tumor Necrosis Factor-alpha; D014612:Vaccines