IDENTIFICATION OF HER-2 NEU CTL EPITOPES USING DOUBLE TRANSGENIC MICEEXPRESSING HLA-A2.1 AND HUMAN CD.8/

The Her-2/neu protooncogene is associated with malignant transformatio n and aggressive disease. Because of its overexpression in tumor cells and because it has been shown to be immunogenic, this protein represe nts an excellent target for T-cell immunotherapy. By identifying poten tial HLA-A2.1-binding peptides from the Her-2/neu sequence, peptides w ere selected as candidate T-cell epitopes. The immunogenicity of each peptide was evaluated by priming double transgenic mice expressing bot h the human (hu) CD8 and HLA-A2.1 molecules with synthetic peptides co rresponding to these sequences. Because of the lack of interaction bet ween murine CD8 and HLA-A2.1, expression of huCD8 on murine cells faci litates recognition of HLA molecules on human tumor cell lines. This l ed to the identification of two peptides that elicit an A2-restricted CTL response, one of which has not been previously identified. Both pe ptide-specific CTL populations were able to specifically lyse A2.1 and Her-2/neu expressing human tumor cells originating from a variety of issues, demonstrating the utility of this murine model in identifying peptides presented by human cells. However, several Her-2/neu peptides previously reported to be immunogenic for human CTL were found not to be immunogenic in transgenic mice. The basis for these discrepancies is discussed. (C) American Society for Histocompatibility and Immunoge netics, 1997.