A loner term goal of this work is to test the hypothesis that a tissue-specific and developmentally regulated antigen may be used for the effective immuno-therapy of prostate cancer. Prostate cancer is the second leading cause of cancer deaths in men and an important disease of the aged. A serious limitation in the past has been the lack of defined and authentic tumor antigens, which would be applicable to humans, yet have the experimental advantages of an animal model. To address these issues the investigators have developed transgenic mice that express human prostate specific antigen (hPSA) in a pattern remarkably similar to humans. In this project they will examine how the specific expression of hPSA in the prostate affects the cell-mediated immune, response to PSA. Using a novel molecular approach, they will determine which PSA epitopes are recognized in the PSA-expressing mice compared to non-transgenic mice. These studies will test the hypothesis that the PSA-CD transgenic mice, in which PSA is a self-antigen, are tolerant to one or more immuno-dominant epitopes, but are capable of responding to this antigen via recognition of a different subset of PSA epitopes that are normally subdominant or cryptic. The PSA epitopes for both CD4 and CD8 cells restricted to mouse class I molecules, as well as those presented by the human HLA-A2 class I molecule, will be determined. They believe they have incorporated a method for not only identifying, but also improving upon tumor-antigen epitopes. Altered peptide ligands with improved MHC binding or improved recognition by the T cell receptor will be created and tested for their ability to stimulate protective responses against tumors expressing native hPSA. Further, using this model they will explore if a vigorous response to PSA results in autoimmune prostatitis. Finally, these results will be incorporated into immunotherapy strategies using mice that develop prostate cancer spontaneously.
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