Peptide-specific cytotoxic T lymphocytes restricted by nonself major histocompatibility complex class I molecules: reagents for tumor immunotherapy.
Studies in melanoma patients have revealed that self proteins can function as targets for tumor-reactive cytotoxic T lymphocytes (CTL). One group of self proteins MAGE, BAGE, and GAGE are normally only expressed in testis and placenta, whilst another group of CTL recognized proteins are melanocyte-specific differentiation antigens. In this study we have investigated whether CTL can be raised against a ubiquitously expressed self protein, mdm-2, which is frequently overexpressed in tumors. The observation that T-cell tolerance is self major histocompatibility complex-restricted was exploited to generate CTL specific for an mdm-2 derived peptide presented by nonself major histocompatibility complex class I molecules. Thus, the allo-restricted T-cell repertoire of H-2d mice was used to isolate CTL specific for the mdm100 peptide presented by allogeneic H-2Kb class I molecules. In vitro, these CTL discriminated between transformed and normal cells, killing specifically Kb-positive melanoma and lymphoma tumors but not Kb-expressing dendritic cells. In vivo, the CTL showed antitumor activity and delayed the growth of melanoma as well as lymphoma tumors in H-2b recipient mice. These experiments show that it is possible to circumvent T-cell tolerance to ubiquitously expressed self antigens, and to target CTL responses against tumors expressing elevated levels of structurally unaltered proteins.
Sadovnikova
E
E
Department of Immunology, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Stauss
H J
HJ
D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003602:Cytotoxicity, Immunologic; D005260:Female; D006183:H-2 Antigens / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007108:Immune Tolerance; D007167:Immunotherapy; D016399:Lymphoma, T-Cell / Q000276:immunology* / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000276:immunology; D009687:Nuclear Proteins; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology*; D010920:Placenta / Q000276:immunology; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D051736:Proto-Oncogene Proteins c-mdm2; D013154:Spleen; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013737:Testis / Q000276:immunology; D014407:Tumor Cells, Cultured
D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2