Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids.
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Gruenewald, Jan, Hunt, Grady S, Dong, Liqun, Niessen, Frank, Wen, Ben, Tsao, Meng-Lin, Perera, Roshan, Kang, Mingchao, Laffitte, Bryan, Azarian, Sassan, Ruf, Wolfram, Nasoff, Marc, Lerner, Richard A, Schultz, Peter and Smider, Vaughn V (2009) Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids. Proceedings of the National Academy of Sciences of the United States of America, 106 (11). pp. 4337-4342. ISSN 1091-6490
Abstract
For more than 2 centuries active immunotherapy has been at the forefront of efforts to prevent infectious disease [Waldmann TA (2003) Nat Med 9:269-277]. However, the decreased ability of the immune system to mount a robust immune response to self-antigens has made it more difficult to generate therapeutic vaccines against cancer or chronic degenerative diseases. Recently, we showed that the site-specific incorporation of an immunogenic unnatural amino acid into an autologous protein offers a simple and effective approach to overcome self-tolerance. Here, we characterize the nature and durability of the polyclonal IgG antibody response and begin to establish the generality of p-nitrophenylalanine (pNO(2)Phe)-induced loss of self-tolerance. Mutation of several surface residues of murine tumor necrosis factor-alpha (mTNF-alpha) independently to pNO(2)Phe leads to a T cell-dependent polyclonal and sustainable anti-mTNF-alpha IgG autoantibody response that lasts for at least 40 weeks. The antibodies bind multiple epitopes on mTNF-alpha and protect mice from severe endotoxemia induced by lipopolysaccharide (LPS) challenge. Immunization of mice with a pNO(2)Phe(43) mutant of murine retinol-binding protein (RBP4) also elicited a high titer IgG antibody response, which was cross-reactive with wild-type mRBP4. These findings suggest that this may be a relatively general approach to generate effective immunotherapeutics against cancer-associated or other weakly immunogenic antigens.
| Item Type: | Article |
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| Additional Information: | author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used |
| Keywords: | retinol-binding protein; tumor necrosis factor; vaccination; p-nitrophenylalanine; genetic code |
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| Date Deposited: | 14 Dec 2009 13:49 |
| Last Modified: | 31 Jan 2013 00:57 |
| URI: | https://oak.novartis.com/id/eprint/1219 |