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 func tion as targets for tumor-reactive cytotoxic T lymphocytes (CTL). One group of self proteins MAGE, BAGE, and GAGE are normally only expresse d in testis and placenta, whilst another group of CTL recognized prote ins are melanocyte-specific differentiation antigens. In this study we have investigated whether CTL can be raised against a ubiquitously ex pressed self protein, mdm-2, which is frequently overexpressed in tumo rs. The observation that T-cell tolerance is self major histocompatibi lity complex-restricted was exploited to generate CTL specific for an mdm-2 derived peptide presented by nonself major histocompatibility co mplex class I molecules. Thus, the allo-restricted T-cell repertoire o f H-2(d) mice was used to isolate CTL specific for the mdm100 peptide presented by allogeneic H-2K(b) class I molecules, In vitro, these CTL discriminated between transformed and normal cells, killing specifica lly K-b-positive melanoma and lymphoma tumors but not K-b-expressing d endritic cells, In vivo, the CTL showed antitumor activity and delayed the growth of melanoma as well as lymphoma tumors in H-2(b) 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 un altered proteins.