TOLERANCE AND IMMUNITY TO MUC1 IN A HUMAN MUC1 TRANSGENIC MURINE MODEL

The human epithelial mucin, MUC1, is a large transmembrane glycoprotei n that is expressed on most simple epithelia. It is overexpressed and aberrantly glycosylated on many human epithelial tumors, including mor e than 90% of human breast cancers, MUC1 is of interest as an immunoth erapy target because patients with breast, ovarian, and pancreatic can cers have T lymphocytes in their tumor-draining lymph nodes that can b e induced to recognize and lyse MUC1-expressing tumor cells, We have p roduced a transgenic mouse model that expresses the human MUC1 molecul e on an inbred C57Bl/6 background to investigate the effect of endogen ous expression of MUC1 on the ability of mice to generate antitumor im munity to MUC1-expressing tumors, Transgenic mice expressed the human transgene in a pattern and level consistent with that observed in huma ns, Transgenic mice were tolerant to stimulation by MUC1 as evidenced by the ability of MUC1-expressing tumor cells to grow in these mice, w hereas MUC1-expressing cells were eliminated from wild-type mice, More over, transgenic mice immunized with MUC1 peptides failed to exhibit i mmunoglobulin class switching to the IgG subtypes, These data suggest that endogenous expression of MUC1 protein by MUC1 transgenic mice ind uces T-cell tolerance to stimulation by MUC1, The transgenic mice will provide a useful model to investigate the mechanisms that regulate im munological tolerance to tumor antigens and will facilitate the invest igation of anti-MUC1 immunotherapy formulations.