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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070218-05
Application #
6172970
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Mccarthy, Susan A
Project Start
1996-09-01
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
5
Fiscal Year
2000
Total Cost
$245,156
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
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
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

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