Document Detail

Immunochemical termination of self-tolerance.
MedLine Citation:
PMID:  18685087     Owner:  NLM     Status:  MEDLINE    
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.
Jan Grünewald; Meng-Lin Tsao; Roshan Perera; Liqun Dong; Frank Niessen; Ben G Wen; Diane M Kubitz; Vaughn V Smider; Wolfram Ruf; Marc Nasoff; Richard A Lerner; Peter G Schultz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-08-06
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  105     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-13     Completed Date:  2008-09-16     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11276-80     Citation Subset:  IM    
Department of Chemistry, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
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MeSH Terms
Amino Acid Substitution*
Antibody Formation / drug effects*,  genetics,  immunology
Communicable Diseases / genetics,  immunology
Endotoxemia / chemically induced,  drug therapy,  genetics,  immunology
Epitopes / genetics,  immunology,  pharmacology
Lipopolysaccharides / toxicity
Metabolic Diseases / genetics,  immunology
Mutation, Missense*
Neoplasms / genetics,  immunology
Nitrophenols / immunology,  pharmacology
Self Tolerance / drug effects*,  genetics,  immunology
Tumor Necrosis Factor-alpha / genetics,  immunology,  pharmacology*
Vaccines / genetics,  immunology
Grant Support
Reg. No./Substance:
0/Epitopes; 0/Lipopolysaccharides; 0/Nitrophenols; 0/Tumor Necrosis Factor-alpha; 0/Vaccines

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