Development of HLA-A2402/K(b) transgenic mice.
HLA-transgenic mice have been developed to facilitate studies of HLA-restricted cytotoxic responses, e.g., for the identification of immunodominant HLA-restricted CTL epitopes and the optimization of peptide or DNA vaccine constructs for human use. We have developed HLA-A2402/K(b)-transgenic mice expressing chimeric human (alpha1 and alpha2 domains of HLA-A2402) and mouse (alpha3, transmembrane and cytoplasmic domains of H-2K(b)) class I molecules. Immunization of these HLA-A2402/K(b)-transgenic mice with various known HLA-A24-restricted immunodominant cancer CTL epitope peptides derived from gp100, MAGE-1, MAGE-3, Her2/neu, CEA and TERT induced HLA-A24-restricted, peptide-specific CTLs. Using these transgenic mice, we identified a novel HLA-A24-restricted CTL epitope, PSA(152-160), encoded by human prostate-specific antigen. Staining with HLA tetramers showed that the cytotoxic activity induced by immunizing with PSA(152-160) in HLA-A2402/K(b) transgenic mice was HLA-A2402-restricted and CD8-dependent. Therefore, PSA(152-160) might be a candidate peptide for vaccination of HLA-A24(+) patients with prostate cancer. Our results suggest that HLA-A2402/K(b) transgenic mice might be useful in the search for HLA-A24-restricted CTL epitopes functioning as human cancer antigens and for the development of peptide-based cancer immunotherapy.
Gotoh
Masashi
M
Research Division, Sumitomo Pharmaceuticals, Osaka, Japan.
Takasu
Hideo
H
Harada
Kenji
K
Yamaoka
Takashi
T
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D005434:Flow Cytometry; D006183:H-2 Antigens / Q000235:genetics* / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D008969:Molecular Sequence Data; D017430:Prostate-Specific Antigen / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013379:Substrate Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection; D019076:Transgenes / Q000235:genetics*
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015234:HLA-A Antigens; D011993:Recombinant Fusion Proteins; D017430:Prostate-Specific Antigen