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Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids

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Overview

related to degree

  • Kang, Mingchao, Ph.D. in Chemistry, Scripps Research 2008 - 2013

authors

  • Grunewald, J.
  • Hunt, G. S.
  • Dong, L. Q.
  • Niessen, F.
  • Wen, B. G.
  • Tsao, M. L.
  • Perera, R.
  • Kang, Mingchao
  • Laffitte, B. A.
  • Azarian, S.
  • Ruf, Wolfram
  • Nasoff, M.
  • Lerner, Richard
  • Schultz, Peter
  • Smider, Vaughn

publication date

  • March 2009

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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.

subject areas

  • Amino Acids
  • Animals
  • Antibody Formation
  • Autoantibodies
  • Autoantigens
  • Immunoglobulin G
  • Immunotherapy
  • Mice
  • Phenylalanine
  • Protein Engineering
  • Self Tolerance
  • T-Lymphocytes
  • Tumor Necrosis Factor-alpha
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Research

keywords

  • genetic code
  • p-nitrophenylalanine
  • retinol-binding protein
  • tumor necrosis factor
  • vaccination
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Identity

PubMed Central ID

  • PMC2657443

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0900507106

PubMed ID

  • 19246393
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Additional Document Info

start page

  • 4337

end page

  • 4342

volume

  • 106

issue

  • 11

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