Abstract
The Wilms' tumour 1 (WT1) molecule was screened in silico for the presence of 15-mer sequences predicted to bind HLA-DRB1(*)0401 (www.syfpeithi.de). Two peptides with the highest binding scores were synthesized (WT12e, PQQMGSDVRDLNALL and WT331, NKRYFKLSHLQMHSR). In vitro sensitization experiments using PBMC and the 15-mer peptides yielded peptide-specific responses against both WT12e and WT331 from six of seven healthy donors. Moreover, four of four different primary CML cell preparations were directly recognized by five different T cell lines, as assessed by IFN-gamma release. These responses were to a great extent blocked by anti-DR monoclonal antibody. These results suggest that WT1 peptides can be selected that are immunogenic for class II-restricted T-cell responses to native tumor cells, and indicate that they may find application in active immunotherapy of CML.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Amino Acid Sequence
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Antigen Presentation
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Antigens, Neoplasm / chemistry*
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / physiology
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Autocrine Communication / drug effects
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Cytokines / analysis
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Drug Design
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Drug Screening Assays, Antitumor
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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HLA-A2 Antigen / immunology
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HLA-DR Antigens / immunology
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HLA-DRB1 Chains
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Humans
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Interferon-gamma / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
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Lymphocyte Activation / drug effects
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Molecular Sequence Data
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Neoplastic Stem Cells / immunology*
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Peptide Fragments / chemical synthesis
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Peptide Fragments / immunology
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Peptide Fragments / pharmacology*
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Protein Binding
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Structure-Activity Relationship
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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WT1 Proteins / chemistry*
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WT1 Proteins / immunology
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WT1 Proteins / physiology
Substances
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Antigens, Neoplasm
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Cytokines
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HLA-A2 Antigen
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HLA-DR Antigens
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HLA-DRB1 Chains
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HLA-DRB1*04:01 antigen
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Peptide Fragments
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WT1 Proteins
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Interferon-gamma
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Granulocyte-Macrophage Colony-Stimulating Factor