E. Sadovnikova et Hj. Stauss, PEPTIDE-SPECIFIC CYTOTOXIC T-LYMPHOCYTES RESTRICTED BY NONSELF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I MOLECULES - REAGENTS FOR TUMOR-IMMUNOTHERAPY, Proceedings of the National Academy of Sciences of the United Statesof America, 93(23), 1996, pp. 13114-13118
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.