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Analogues of CTL epitopes with improved MHC class-I binding capacity elicit anti-melanoma CTL recognizing the wild-type epitope.

Abstract
The MHC class-I binding affinity of an epitope is an important parameter determining the immunogenicity of the peptide-MHC complex. In order to improve the immunogenicity of an epitope derived from melanocyte lineage-specific antigen gp100, we performed amino-acid substitutions within the epitope and assayed both HLA-A*0201 binding and CTL recognition. Anchor replacements towards the HLA-A*0201 peptide-binding motif gave rise to peptides with higher HLA-A*0201 binding capacity compared to the wild-type epitope. In addition, several of the gp100 154-162 epitope-analogues were more efficient at target-cell sensitization for lysis by anti-gp100 154-162 CTL compared to the wild-type epitope. These altered gp100 154-162 epitopes were subsequently tested for their capacity to induce CTL responses in vivo using HLA-A*0201/Kb transgenic mice, and in vitro using HLA-A*0201 + donor-derived lymphocytes. Interestingly, the peptide-specific CTL obtained, which were raised against the different gp100 154-162 epitope-analogues, displayed cross-reactivity with target cells endogenously processing and presenting the native epitope. These data demonstrate that altered epitopes can be exploited to elicit native epitope-reactive CTL. The use of epitope-analogues with improved immunogenicity may contribute to the development of CTL-epitope based vaccines in viral disease and cancer.
AuthorsA B Bakker, S H van der Burg, R J Huijbens, J W Drijfhout, C J Melief, G J Adema, C G Figdor
JournalInternational journal of cancer (Int J Cancer) Vol. 70 Issue 3 Pg. 302-9 (Jan 27 1997) ISSN: 0020-7136 [Print] United States
PMID9033632 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Epitopes, T-Lymphocyte
  • HLA-DQ Antigens
  • HLA-DQ alpha-Chains
  • HLA-DQA1 antigen
  • Histocompatibility Antigens Class I
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • PMEL protein, human
  • Pmel protein, mouse
  • gp100 Melanoma Antigen
Topics
  • Animals
  • Cross Reactions (immunology)
  • Epitopes, T-Lymphocyte (immunology)
  • HLA-DQ Antigens (immunology)
  • HLA-DQ alpha-Chains
  • Histocompatibility Antigens Class I (immunology)
  • Humans
  • Lymphocytes, Tumor-Infiltrating (immunology)
  • Melanoma (immunology)
  • Membrane Glycoproteins (chemistry, immunology)
  • Mice
  • Mice, Transgenic
  • Neoplasm Proteins (chemistry, immunology)
  • T-Lymphocytes, Cytotoxic (immunology)
  • Tumor Cells, Cultured
  • gp100 Melanoma Antigen

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