Immunology Graduate Group
Yvonne Paterson, Ph.D.
Department of Microbiology
Office Phone: 215-898-3461
Email: yvonne@mail.med.upenn.edu
Education:
B.Sc., Biochemistry, University of Manchester
M.Sc., Biochemistry, University of Manchester
B.A., Mathematics / Philosophy, Australian National University
Ph.D., Biochemistry, Melbourne University
Post Doctoral Fellow, Cornell University
Research Interests
Molecular biological and cellular approaches to inducing and regulating T cells in the treatment and prevention of infectious and neoplastic disease
Research 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.
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| How antigens secreted by L. monocytogenes access both the MHC class I and class II pathways for antigen processing. (A) after phagocytosis into an antigen presenting cell, L. monocytogenes is either (B) destroyed within a lysosomal compartment, where peptides may be loaded onto MHC class II molecules, or (C) it escapes into the cytoplasm of the cell. In the cytosolic compartment, Listeria can grow and any protein it secretes can be processed by proteosomes into peptides that will be transported (D) to the endoplasmic reticulum for loading onto MHC class I molecules. (E) In the cytosolic compartment, Listeria reorganizes the host cells actin into "tails" which propel it around the cell and to the cell's periphery. There it can be internalized by a neighboring cell, and by breaking through, two plasma membranes colonize this cell. |
Recent Publications
Pan, Z-K, Ikonomidis, G., Lazenby, A., Pardoll, D., and Y. Paterson. A recombinant Listeria monocytogenes vaccine expressing a model tumour antigen protects mice against lethal tumour challenge and causes regression of established tumours. Nature Medicine 1:471-477. 1995
Mata, M., Yao, Z., Zubair, A., Syres, K. and Y. Paterson, Evaluation of a recombinant Listeria monocytogenes expressing an HIV protein that protects mice against viral challenge. Vaccine.19:1435-45, 2001.
Weiskirch, L. M., Pan, Z.-K., and Y. Paterson The tumor recall response of anti-tumor immunity primed by a live, recombinant L. monocytogenes vaccine is comprised of multiple effector mechanisms. Clin. Immunol. 98: 346 - 357, 2001.
Beatty, G. and Y. Paterson, IFN-gamma dependent inhibition of tumor angiogenesis by tumor infiltrating CD4+ T cells requires tumor responsiveness to IFN-gamma. J. Immunol. 166:2276-2282, 2001
Gunn, G.R., Zubair, A., Peters, C.H., Pan, Z.-K., Wu, T.-C. and Y. Paterson, Two L. monocytogenes vaccine vectors that express different molecular forms of HPV-16 E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16. J. Immunol. 167:6471-6479, 2001
Lamikanra, A., Pan, Z.-K., Isaacs, S., Wu T.-C., and Y. Paterson. The ability to induce the regression of established HPV-16 immortalized tumors in vivo by vaccinia viruses expressing different forms of HPV-16 E7 correlates with enhanced CD8+ T cell responses that home to the tumor site. J. Virol. 75:9654-9664, 2001.
Matthews, A. E., Weiss, S. R., Shlomchik, M.J., Hannum, L.G., Gombold, J. L. and Y. Paterson. Antibody is required for clearance of infectious murine hepatitis virus A59 from the CNS but not the liver. J. Immunol. 167:5254-63, 2001.
Matthews, A. E., Lavi, E., Weiss, S. R., and Y. Paterson. Neither B cells nor T cells are required for CNS demyelination in mice persistently infected with MHV-A59. J. NeuroVirol., 8:260-267, 2002
Peters, C., Xiaohui Peng, Douven D., Zhen-Kun Pan and Y. Paterson. 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
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