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New TRP-2-derived T helper epitopes identified in HLA-DRB1*0301 transgenic mice elicit spontaneous T cell responses in HLA-DRB1*03 and HLA-DRB1*04 melanoma patients

  • M Song1Email author,
  • W Osen1,
  • D Thomas1,
  • N Daniel2,
  • XD Nguyen3,
  • J Mueller-Berghaus1,
  • H Kropshofer2,
  • D Schadendorf1 and
  • A Paschen1
Cancer Cell International20044(Suppl 1):S51

Received: 28 April 2004

Published: 1 July 2004


Melanoma PatientProtein ImmunizationActive ImmunotherapyPeptide ImmunizationRestricted Peptide

Antigen-specific cytotoxic CD8+ T lymphocytes (CTLs) are effective mediators of destructive anti-melanoma immunity but primary CTL-sensitisation and establishment of CTL-memory are dependent on the helper activity of antigen-specific CD4+ T lymphocytes. Therefore, active immunotherapy of melanoma patients should ideally target antigen-specific CD8+ and CD4+ T cells in order to achieve effective anti-tumor CTL immunity. Identification of tumor antigen epitopes is a prerequisite for specific T-cell targeting in the course of vaccination and for vaccine evaluation. But in contrast to HLA-class I restricted peptide ligands only a few HLA-class II-presented epitopes are characterized. We used computer algorithms and HLA-DRB1*0301 (HLA-DR3) transgenic mice to identify epitopes derived from the differentiation antigen tyrosinase-related protein-2 (TRP-2). Three potential HLA-DR3-restricted epitopes were predicted from the TRP-2 protein sequence, two of the corresponding synthetic peptides exhibited HLA-DR3 binding capacity, but only one sequence (Pep1) specifically activated CD4+ T cells in HLA-DR3 transgenic mice after peptide immunization. Processing of an epitope located in the Pep1 sequence from the TRP-2 antigen was subsequently demonstrated by TRP-2 protein immunization. Pep1-specific CD4+ T cells could also be induced in vitro in human T cell cultures obtained from the peripheral blood of normal HLA-DRB1*0301 donors. Interestingly, in vivo sensitized Pep1-specific T cells were also detectable in the peripheral blood of HLA-DRB1*03 and HLA-DRB1*04 melanoma patients verifying Pep1 as a target of spontaneous T cell responses.

Authors’ Affiliations

Skin Cancer Unit of the German Cancer Research Center Heidelberg at the University Hospital of Mannheim, Mannheim, Germany
Roche Center for Medical Genomics, Basel, Switzerland
Institute of Transfusion Medicine and Immunology, Mannheim, Germany


© Author(s); licensee BioMed Central Ltd. 2004