Abnormally glycosylated lipids and proteins often occur in tumors and are identifiable by monoclonal antibodies as tumor-associated antigens. Recent observations suggest that carbohydrate-specific, cell-mediated immunity involving CD4+ and/or CD8+ T-cells can be induced, and that the carbohydrate-specific T-cells can have anti-tumor activity. In this application the investigator describes a plan to systematically determine the optimal peptide structure to which a hapten (either TNP or oligosaccharide can be conjugated, in order to elicit a cytotoxic T-cell response that is specific for the haptenic (oligosaccharide) moiety and that does not recognize the peptide backbone structure to which it is conjugated. He will determine whether that is promiscuous or independent of an antigen-presenting MHC specificity. He will evaluate the extent to which MHC recognition is involved by evaluating the recognition of glycopeptides presented by mutant or allo-MHC specificities, and by evaluating the possibility of MHC-independent recognition of the hapten conjugates. Finally, using tumor-associated carbohydrates as haptenic determinants, glycopeptides will be used as immunogens to determine whether significant tumor immunity can be generated with such antigens in murine tumor models.
| Franco, A; Yokoyama, T; Huynh, D et al. (1999) Fine specificity and MHC restriction of trinitrophenyl-specific CTL. J Immunol 162:3388-94 |
| Wang, R; Wang-Zhu, Y; Gabaglia, C R et al. (1999) The stimulation of low-affinity, nontolerized clones by heteroclitic antigen analogues causes the breaking of tolerance established to an immunodominant T cell epitope. J Exp Med 190:983-94 |
