Primary Appointment:
 Microbiology & Immunology

GEBS Cluster Affiliations:
 Biochemistry, Molecular Biology, & Genetics - BMBG
 Immunology, Microbiology, and Vaccine Biology - IMV
 Molecular Oncology and Cancer Biology - MOCB

University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box 704
Rochester, New York 14642

Phone: (716) 275-3405
Fax: (716) 461-4019 E-Mail: John_Frelinger@urmc.rochester.edu

Generation of Organ Specific Immunity Using Prostate Specific Antigen (PSA) as a Model Tumor Antigen.

The paucity of animal models for prostate tumors, has greatly limited progress in the understanding and treatment of this cancer. A group of investigators, including myself, Dr. Lord, and Dr. Barth, has begun a collaborative project to establish models of prostate cancer in mice so that we can address issues of immunological tolerance and immunotherapy strategies. To develop mouse models relevant to prostate cancer, the regulatory regions of PSA have been used to create a gene cassette which has been used to drive gene expression in the prostate. We have targeted prostate-specific expression of two genes in transgenic mice, the large T antigen of SV40 and human PSA. These mice will allow us to address the crucial issue of self-tolerance and how it may affect tumor immunity. It has become clear that even with multiple mechanisms of establishing and maintaining tolerance, tolerance is not absolute. We hypothesize 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, we will use transgenic mice lines we have developed which specifically express human PSA in the prostate and investigate how this expression affects their ability to generate CTL responses to human PSA. These studies also will be performed using tumor cell lines that express PSA, as well as with tumors which develop spontaneously in the transgenic mice expressing large T antigen in the prostate. Further, by using HLA transgenic mice, we can investigate immune responses in systems with direct relevance to immunotherapy. The ultimate clinical use of these approaches will be to generate specific CTL that target a potentially dispensable organ, such as the prostate. These studies will have implications for the treatment of other cancers and will broaden our understanding of various important aspects of the process of autoimmunity.

Ostberg JR. Dragone LL. Borrello MA. Phipps RP. Barth RK. Frelinger JG. Expression of mouse CD43 in the B cell lineage of transgenic mice causes impaired immune responses to T-independent antigens. European Journal of Immunology. 27(9):2152-9, 1997.

McEvoy LM. Sun H. Frelinger JG. Butcher EC. Anti-CD43 inhibition of T cell homing. Journal of Experimental Medicine. 185(8):1493-8, 1997.

Wei C. Willis RA. Tilton BR. Looney RJ. Lord EM. Barth RK. Frelinger JG. Tissue-specific expression of the human prostate-specific antigen gene in transgenic mice: implications for tolerance and immunotherapy. PNAS, USA. 94(12):6369-74, 1997.