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 (Tyr⁸⁶) of murine tumor necrosis factor-α (mTNF-α) to p-nitrophenylalanine (pNO₂Phe) induced a high-titer antibody response in mice, whereas no significant antibody response was observed for a Tyr⁸⁶ → Phe mutant. The antibodies generated against the pNO₂Phe are highly cross-reactive with native mTNF-α 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.