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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
11
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pubmed:dateCreated |
2009-3-18
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-10404159,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-10837052,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-11593016,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-11604536,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-12089323,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-12484775,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-12496961,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-14264273,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-14745228,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-15196886,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-15485331,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-15588697,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-15682451,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-16809734,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-17075816,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-17237348,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-17632054,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-18004753,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-18080016,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-18173373,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-18305483,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-18424715,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-18508549,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-18685087,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-2217163,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-6153101,
http://linkedlifedata.com/resource/pubmed/commentcorrection/19246393-9309429
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1091-6490
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pubmed:author |
pubmed-author:AzarianSassanS,
pubmed-author:DongLiqunL,
pubmed-author:GrünewaldJanJ,
pubmed-author:HuntGrady SGS,
pubmed-author:KangMingchaoM,
pubmed-author:LaffitteBryan ABA,
pubmed-author:LernerRichard ARA,
pubmed-author:NasoffMarcM,
pubmed-author:NiessenFrankF,
pubmed-author:PereraRoshanR,
pubmed-author:RufWolframW,
pubmed-author:SchultzPeter GPG,
pubmed-author:SmiderVaughn VVV,
pubmed-author:TsaoMeng-LinML,
pubmed-author:WenBen GBG
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pubmed:issnType |
Electronic
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pubmed:day |
17
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pubmed:volume |
106
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4337-42
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:19246393-Amino Acids,
pubmed-meshheading:19246393-Animals,
pubmed-meshheading:19246393-Antibody Formation,
pubmed-meshheading:19246393-Autoantibodies,
pubmed-meshheading:19246393-Autoantigens,
pubmed-meshheading:19246393-Immunoglobulin G,
pubmed-meshheading:19246393-Immunotherapy,
pubmed-meshheading:19246393-Mice,
pubmed-meshheading:19246393-Phenylalanine,
pubmed-meshheading:19246393-Protein Engineering,
pubmed-meshheading:19246393-Self Tolerance,
pubmed-meshheading:19246393-T-Lymphocytes,
pubmed-meshheading:19246393-Tumor Necrosis Factor-alpha
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pubmed:year |
2009
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pubmed:articleTitle |
Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids.
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pubmed:affiliation |
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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