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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070218-03
Application #
2769849
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Mccarthy, Susan A
Project Start
1996-09-01
Project End
1999-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Rochester
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Fisher, Terrence L; Nocera, MaryAnn; Willis, Richard A et al. (2002) Generation of monoclonal antibodies specific for human kallikrein 2 (hK2) using hK2-expressing tumors. Prostate 51:153-65
Brown, D M; Fisher, T L; Wei, C et al. (2001) Tumours can act as adjuvants for humoral immunity. Immunology 102:486-97
Skrincosky, D; Willis, R A; Hocknell, P K et al. (2001) Epitope mapping of human herpesvirus-7 gp65 using monoclonal antibodies. Arch Virol 146:1705-22
Turner, M J; Abdul-Alim, C S; Willis, R A et al. (2001) T-cell antigen discovery (T-CAD) assay: a novel technique for identifying T cell epitopes. J Immunol Methods 256:107-19
Patel, D; Frelinger, J; Goudsmit, J et al. (2001) In vitro assay for site-specific proteases using bead-attached GFP substrate. Biotechniques 31:1194, 1196, 1198 passim
Egan, R M; Yorkey, C; Black, R et al. (2000) In vivo behavior of peptide-specific T cells during mucosal tolerance induction: antigen introduced through the mucosa of the conjunctiva elicits prolonged antigen-specific T cell priming followed by anergy. J Immunol 164:4543-50
Storozynsky, E; Woodward, J G; Frelinger, J G et al. (1999) Interleukin-3 and granulocyte-macrophage colony-stimulating factor enhance the generation and function of dendritic cells. Immunology 97:138-49
Wei, C; Callahan, B P; Turner, M J et al. (1998) Regulation of human prostate-specific antigen gene expression in transgenic mice: evidence for an enhancer between the PSA and human glandular kallikrein-1 genes. Int J Mol Med 2:487-96
Willis, R A; Wei, C; Turner, M J et al. (1998) A transgenic strategy for analyzing the regulatory regions of the human prostate-specific antigen gene: potential applications for the treatment of prostate cancer (Review). Int J Mol Med 1:379-86
Lord, E M; Frelinger, J G (1998) Tumor immunotherapy: cytokines and antigen presentation. Cancer Immunol Immunother 46:75-81

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