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Member Information
Yvonne Paterson, PhD
Professor, Department of Microbiology
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Website(s): http://www.med.upenn.edu/micro/faculty/paterson.html
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Keywords: Vaccine development, HIV/SIV, Listeria monocytogenes, prime/boost strategies
Research and/or Clinical Interests:
Using Listeria monocytogenes as a vaccine vector to target HIV and SIV antigens to the immune system.
Summary:
Most of the research performed in the Paterson laboratory is dedicated to providing cures for, or protection against, neoplastic and infectious disease. Our immunological work is based on a long standing interest in the properties of proteins that render them immunogenic and how such immunogenicity may be modulated in vivo. In the case of the immunoglobulin receptor on B cells both the antigenic site on the protein antigen and the binding site of the immunoglobulin are topographic surfaces. However, in the case of the T cell receptor the antigenic region of the protein is a peptide derived by cellular processing and expressed on the surface of an antigen presenting cell associated with a molecule of the major histocompatibility complex (MHC). The cellular compartment in which the T cell epitope is generated determines whether it emerges at the cell surface bound to MHC class I or II molecules and, therefore, what type of T cell response is elicited. There have been enormous advances made in the last few years in our understanding of the molecular and cellular machinery that governs the presentation of antigens to the immune system. In our laboratory, we are applying this knowledge to the development of strategies of immune regulation for a number of disease models. We are attempting to enhance the immune response in the design of more effective vaccines against viral diseases, such as HIV, and against tumor cells. To do this we are using a facultative intracellular bacterium, Listeria monocytogenes, which has the unusual ability to live and grow in the cytoplasm of the cell. We have shown that recombinant forms of this organism which have been transformed to express foreign antigens are excellent vectors for targeting the antigen to the class I pathway and inducing cell mediated immune responses which cause the elimination of established macroscopic tumors. We have also discovered that fusing an antigen to some bacterial proteins enhances their immunogenicity. This finding opens up novel, and perhaps safer, avenues to cancer immunotherapy. We are currently looking at a number of different approaches to carry these fusion proteins to the immune system for cancer immunotherapy, including protein plus adjuvant, vaccinia virus and pulsed dendritic cells. Cancers to which we are directing our technology currently include cervical cancer, breast cancer and lymphoma.
Representative Publications:
Mata, M., Travers, P., Liu, Q., Frankel, F.R. Paterson Y. The MHC class I restricted immune response to HIV-GAG in BALB/c mice selects an epitope which does not have a predictable MHC binding motif and binds to Kd through interactions between a glutamine at P3 and pocket D. J. Immunol. 161: 2985-2993. 1998
Argyris, E., Venkateswaran, P.S., Vanderkooi, J.M., Kay, B.K., Paterson Y. The connection domain is implicated in metalloporphyrin binding and inhibition of HIV RT. J. Biol. Chem. 274: 1549 - 1556. 1999
Mata, M., Paterson Y. Th1 T cell responses to HIV-1 Gag protein delivered by a Listeria monocytogenes vaccine are similar to those induced by endogenous listerial antigens. J. Immunol. 163:1449 - 1456. 1999
Mata, M., Yao, Z., Zubair, A., Syres, K., Paterson Y. Evaluation of a recombinant Listeria monocytogenes expressing an HIV protein that protects mice against viral challenge. Vaccine.19:1435-45, 2001.
Argyris, E. G., Vanderkooi, J.M., Paterson Y. Mutagenesis of key residues identifies the connection subdomain of HIV-1 RT as the site of inhibition by heme. Eur. J. Biochem. 268:925-931, 2001.
Peters, C. Paterson, Y. Enhancing the immunogenicity of bioengineered Listeria monocytogenes by passaging through live animal hosts. Vaccine. 21:1187-94. 2003
Peters, C., Xiaohui Peng, Douven D., Pan, Z-K., Paterson Y. The induction of HIV-Gag specific CD8 + T cells in the spleen and GALT by parenteral or mucosal immunization using recombinant Listeria monocytogenes -HIV-Gag . . J. Immunol 170:5176-5187. 2003
Boyer, J. D., Robinson, T. M., Peng, X., Johnson, R. S., Pavlakis, G., Carlarota, S., Lewis, M., Weiner, D., Paterson, Y. DNA Prime Listeria Boost Induces a Cellular Immune Response to SIV Antigens in the Rhesus Macaque Model. Submitted.
Argyris, E. G., Zhou, N., Fang, J., Acheampong, E., Mukhtar, M., Root, M. J., Paterson , Y., Pomerantz R.J. A Novel Metalloporphyrin Inactivates HIV-1 by Both Blocking Viral Entry and Inhibiting Reverse Transcription. Submitted
