There is currently a paucity of animal models for prostate tumors. One of the goals of this project is to establish a mouse model of prostate tumors. This will enable the Principal Investigator to take advantage of the wealth of genetic and immunologic reagents for this species and enable him to test potential strategies for immunotherapy. To develop this model the Principal Investigator will isolate the human prostate specific antigen (PSA) gene and its regulatory regions. These regulatory regions will then be used to drive gene expression in the mouse prostate via transgenic technology. Human genes often replicate their tissue specific expression patterns in mice. This approach will also be used to target expression of the SV40 T antigen to the mouse prostate. The expected result is that prostatic tumors will develop. The resulting tumor lines will be valuable reagents as models for prostate cancer. In addition, the Principal Investigator will use the tumor lines in experiments on anti-cancer immunotherapeutic approaches. The prostate specific expression of human PSA will be used to investigate the breaking of tolerance, as assessed by the generation of PSA specific CTL, which would, in turn, generate targeted autoimmunity. Self tolerance has been shown to depend on several mechanisms. Even so, it is clear that tolerance is not absolute. The Principal Investigator hypothesizes that it is possible to direct an autoimmune response in an organ or tissue specific fashion by inducing an immune response to organ specific antigens. To examine this hypothesis the current study will: 1) develop an expression vector that will drive expression of genes in the prostate; 2) develop transgenic mice specifically expressing PSA in the prostate; 3) investigate the ability to elicit CTL responses to PSA in vivo in HLA-A2 expressing mice; and 4) determine whether potent immunization strategies can enhance CTL development and tumor rejection even in PSA expressing animals. The ultimate clinical use of these approaches will be to generate specific CTL that would target a potentially dispensable organ, such as the prostate. For example, the prostate specific CTL could be used for the elimination of metastatic prostatic cells after removal of the gland.
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