Immunochemical termination of self-tolerance.

نویسندگان

  • 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
چکیده

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.

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عنوان ژورنال:
  • Proceedings of the National Academy of Sciences of the United States of America

دوره 105 32  شماره 

صفحات  -

تاریخ انتشار 2008