 Ph.D.
(1980) |
John
Frelinger
Professor of Microbiology & Immunology and of Oncology Primary Appointment: GEBS Cluster Affiliations: |
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| Contact Information: | ||
| University
of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box 672 Rochester, New York 14642 |
Medical Center 2-3015 Phone: (585) 275-3405 Fax: (585) 461-4019 E-Mail: John_Frelinger@urmc.rochester.edu |
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- Research Focus
- T cell immunity to tumors and pathogens
- Research Overview
- My laboratory has a number of interests united by the common theme of T cell recognition. One focus of research has been the generation and maintenance of effective T cell responses to tumors. It has become apparent that anti-tumor responses can be directed against differentiation antigens. Thus, even with multiple mechanisms of establishing and maintaining tolerance, tolerance is not absolute. We hypothesize that it is possible to direct an effective response against tumors by inducing an autoimmune 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 using novel immunization strategies. In this light, we have been working on developing novel viral vectors for immunization. Helper free herpes amplicons, plasmid based vectors that have an extremely large coding capacity, are attractive viral vaccine candidates for expressing recombinant proteins in vivo for immunization. The amplicon system has particular promise since it encodes no viral gene products and we have shown it very effectively infects dendritic cells. In collaboration with Edith Lord and in conjunction with Tom Foster's laboratory in the Department of Imaging Sciences, we have devised imaging approaches to look at the early steps in immunization and at the effector T cells generated. These studies will contribute to the rational design of immunotherapy for tumors as well as for HIV. We also believe that many of the techniques and approaches will be applicable to other infectious agents as well. In this regard, we are collaborating with investigators at University of North Carolina to identify T cell epitopes of Francisella tularensis. Francisella tularensis (FT) is a gram negative bacterium that is able to infect a wide range of mammalian hosts. FT has several properties that suggest could be developed as a biological weapon, including its ability to be aerosolized and its low LD50. Indeed, it has been asserted that FT was used as a bioweapon in World War II. Unfortunately relatively little information is available concerning the detailed cellular mechanism of resistance to re-infection either in humans or in experimental animals. However, as expected for a pathogen that grows largely intracellularly, T cells are believed to be a critical component in resistance to reinfection and recovery from primary infection. My laboratory has developed a technique called the TCAD ( the T-Cell antigen discovery technique) to identify and improve T cell epitopes, originally in the context of tumor vaccines. We have recently modified this system to large-scale screens for the identification of T cell epitopes from FT using this system which takes advantage of the tremendously enhanced efficiency particulate antigen cross-priming and a novel reporter system of T cell activation. It is hoped that the identification of the T cell epitopes recognized will yield to a batter understanding of the nature of a protective response and ultimately a defined vaccine.
- Recent Publications
- Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol. 2008 Mar 1;180(5):3132-9
- Wei C, Callahan BP, Turner MJ, Willis RA, Lord EM, Barth RK, Frelinger JG 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. 1998 Oct;2(4):487-96
- Santos K, Simon DA, Conway E, Bowers WJ, Mitra S, Foster TH, Lugade A, Lord EM, Federoff HJ, Dewhurst S, Frelinger JG. "Spatial and temporal expression of herpes simplex virus type 1 amplicon-encoded genes: implications for their use as immunization vectors." Hum Gene Ther. 2007 Feb;18(2):1-13.
- Malboeuf CM, Simon DA, Lee YE, Lankes HA, Dewhurst S, Frelinger JG, Rose RC. "Human papillomavirus-like particles mediate functional delivery of plasmid DNA to antigen presenting cells in vivo." Vaccine. 2007 Jan 22;
- Ramanayake T, Simon DA, Frelinger JG, Lord EM, Robert J. "In vivo study of T-cell responses to skin alloantigens in Xenopus using a novel whole-mount immunohistology method." Transplantation. 2007 Jan 27;83(2):159-66.
- Mitra S, Cassar SE, Niles DJ, Puskas JA, Frelinger JG, Foster TH "Photodynamic therapy mediates the oxygen-independent activation of hypoxia-inducible factor 1{alpha}." Mol Cancer Ther. 2006 Dec;5(12):3268-74
- Santos K, Duke CM, Rodriguez-Colon SM, Dakwar A, Fan S, Keefer MC, Federoff HJ, Frelinger JG, Bowers WJ, Dewhurst S "Effect of promoter strength on protein expression and immunogenicity of an HSV-1 amplicon vector encoding HIV-1 Gag." Vaccine. 2006 Nov 15;
- Gerber SA, Rybalko VY, Bigelow CE, Lugade AA, Foster TH, Frelinger JG, Lord EM "Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth." Am J Pathol. 2006 Nov;169(5):1739-52
- Wagner VE, Frelinger JG, Barth RK, Iglewski BH. "Quorum sensing: dynamic response of Pseudomonas aeruginosa to external signals." Trends Microbiol. 2006 Feb;14(2):55-8. Epub 2006 Jan 6.
- Lugade AA, Moran JP, et al. "Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor." J Immunol. 2005 Jun 15;174(12):7516-23.
- Gerber, S. A., M. J. Turner, et al. "Characterization of a lymph node within the mouse prostate: Detailed analysis using whole mount histology." Prostate 63(2): 105-16, 2005.
- Lugade, A. A., J. P. Moran, et al. "Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor." J Immunol 174(12): 7516-23, 2005.
- Mitra S, Goren EM, Frelinger JG, Foster TH. "Activation of heat shock protein 70 promoter with meso-tetrahydroxyphenyl chlorin photodynamic therapy reported by green fluorescent protein in vitro and in vivo." Photochem Photobiol. 78:615-22, 2003.
- Moran JP, Gerber SA, Martin CA, Frelinger JG, Lord EM. Transfection of the genes for interleukin-12 into the K1735 melanoma and the EMT6 mammary sarcoma murine cell lines reveals distinct mechanisms of antitumor activity. Int J Cancer. 106:690-8, 2003.
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