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Research
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  • Department Research
  • Cutaneous Immunobiology and Genetic Immunization - Summary
  • Cutaneous Immunobiology and Genetic Immunization - References
  • Dendritic Cell Biology; Dendritic Cell Vaccines and Immunotherapies.
  • Particulate Antigen Vaccines and Immunotherapies.
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    Overview Back to top
     
     
    The Department’s research program has made several innovative contributions in the areas of science and technology related to clinical medicine, particularly in the areas of vaccine design and immunotherapy. These accomplishments have been recognized by publication in the most highly regarded peer-reviewed medical journals, including top ranked Nature Journals journal "Nature Medicine” and “Nature Immunology”, and by considerable external funding through competitively awarded NIH research grants. This work has also resulted in considerable intellectual property, and many of these innovative discoveries are now being actively developed by several biotechnology companies. Major areas of investigation within the Department and selected Department research accomplishments include those summarized below.

    In addition to these well established research programs, the Department has recently established new, competitively-funded initiatives in Melanoma Immunotherapy, Cutaneous T-cell Lymphoma Immunotherapy, HIV Immunotherapy, and Vaccine Development for Biodefense. In collaboration with Dr. Simon Watkins, Department investigators are currently developing novel applications of confocal microscopy for the real-time, in situ diagnosis of cutaneous diseases, including cutaneous cancers such as melanoma and basal cell carcinoma. These imaging efforts are summarized in recent Pittsburgh Post Gazette articles (Getting to the (focal) Point, Seeing Skin Deep,

    Seeing Skin Deep

    Confocal Applications

     
     
    Cutaneous Immunobiology and Genetic Immunization - Summary Back to top
     
    Click to view large image   
     
    In studies published in the journals Nature Medicine and Gene Therapy, Department investigators demonstrated that a novel genetic immunization strategy which utilizes a gene gun can be used to effectively transfect dendritic cells in human skin in vivo, resulting in the induction of potent immune responses. The ability to transfect dendritic cells offers considerable opportunity for immune manipulation, with potential practical applications for the treatment of cancer, infectious diseases, and autoimmune disease. This technology is now being evaluated in clinical trials and is also described in the The Pittsburgh Post- Gazette article “These Gold Bullets Help Target Attack on Cancer”.
    In pioneering studies published in journal Nature Immunology, Department investigators describe the discovery of a precursor cell in skin that has the potential to point the way to manipulating the immune system. This accomplishment has broad implications for the future development of immunotherapies designed to prevent or treat a variety of cancers, as well as the development of immunotherapies designed to treat autoimmune mediated diseases and facilitate transplantation. In addition this discovery is likely to have significant impact on the development of tissue engineering, particularly in the development of engineered human skin. This discovery is summarized in the Pittsburgh Post Gazette article "Under Your Skin". See Article

     
     
    Cutaneous Immunobiology and Genetic Immunization - References Back to top
     
     
    References:

    Condon, C, Watkins, S, Celluzzi C., Thompson, K.M, and Falo, LD, Jr. DNA-based immunization by in vivo transfection of dendritic cells. Nature Medicine 2(10): 1996. ABSTRACT

    Falo LD Jr. Targeting the Skin for Genetic Immunization.
    Proceedings of the Association of American Physicians. 111(3): 211-9. 1999.
    ABSTRACT

    Larregina AT and Falo, LD, Jr. Generating and regulating immune responses through cutaneous gene therapy. Human Gene Therapy, 11:2301-2305, 2000
    ABSTRACT

    Larregina AE, Stolinski, L., Watkins SC, Storkus WJ and Falo, LD. Jr. Transfection and Activation of Dendritic Cells in Human Skin. Gene Therapy 8:608-617. 2001.
    ABSTRACT

    Larregina, Adriana T., Morelli, Adrian E., Spencer, Lori A., Logar, Alison J., Watkins, Simon C., Thomson, Angus W. and Falo, L D., Jr. Dermal-resident CD14+ cells differentiate into Langerhans cells
    Nature Immunology, 12, 1151-1158. 2001.
    ABSTRACT

    Larregina AE, Stolinski, L., Watkins SC, Storkus WJ and Falo, LD. Jr. Transfection and Activation of Dendritic Cells in Human Skin. Gene Therapy 8:608-617. 2001.
    ABSTRACT

    Morel PA, Falkner D, Plowey J, Larregina AT and Falo LD, Jr.DNA immunization: altering the cellular localisation of expressed protein and the immunisation route allows manipulation of the immune response, Vaccine, In Press, 2003.

    Larregina AT, Morelli AE, Tkacheva O, Erdos G, Donahue C, Watkins SC, Thomson AW, and Falo, LD, Jr.
    Highly efficient expression of transgenic proteins by naked DNA transfected dendritic cells through terminal differentiation. Blood, 10.1182/blood-2003-02-0524. 2003
    ABSTRACT
     
     
    Dendritic Cell Biology; Dendritic Cell Vaccines and Immunotherapies. Back to top
     
     
    Department investigators have published a series of articles demonstrating the feasibility of utilizing dendritic cells for Immunoregulation, including the development of adoptive transfer therapies for cancer and infectious diseases. This series of pioneering experiments was published in very high-profile journals including Nature Medicine, the Journal of Experimental Medicine, and as a “Cutting-Edge” article in the Journal of Immunology. This work and ongoing studies are the basis for several ongoing clinical trials at the University of Pittsburgh and at other major medical centers. This work was reviewed in a front page Pittsburgh Post Gazette article (New Weapon Emerges in Cancer Battle). and is being commercially developed through the University of Pittsburgh and affiliated spin-off companies.

    References:

    Celluzzi, C, Mayordomo, JI, Storkus WJ, Lotze MT, Falo LD Jr., Peptide-pulsed dendritic cells induce antigen specific CTL-mediated protective tumor immunity. J. Exp. Med. 183:283-287. 1996.
    ABSTRACT

    Mayordomo, JI, Zorina T, Storkus, WJ, Celluzzi, CM, Falo LD Jr., Ildstad ST, Kast MW, DeLeo AB, and Lotze MT. Bone marrow-derived dendritic cells pulsed with tumor peptides effectively treat established murine tumors.
    Nature Medicine. 1:1297-1302. 1995.
    ABSTRACT

    Celluzzi, C. and Falo, LD, Jr. Cutting Edge: Physical Interaction Between Dendritic Cells and Tumor Cells Results in an Immunogen That Induces protective and Therapeutic Tumor Rejection.
    J. Immunol.(Cutting Edge). 160(7): 3081-3085.1998.
    ABSTRACT

    Morelli, A.E., Zahorchak, A.F., Larregina, A.T., Colvin, B.L., Logar, A.J., Takayama, T., Falo, LD., Jr., and Thompson A.W. Regulation of cytokine production by myeloid dendritic cells in relation to differentiation and terminal maturation in response to LPS or CD40 ligation. Blood, 98:5, 1521-23. 2001.
    ABSTRACT

    Morelli, AE, Larregina, AT, Shufesky, WJ, Zahorchak, AF, Logar, AJ, Papworth, GD, Wang, Z. Watkins, SC, Falo, JD, Jr., and Angus W. Thomson. Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production. Bloo., 101:2, 611-620, 2003.
    ABSTRACT

     
     
    Particulate Antigen Vaccines and Immunotherapies. Back to top
     
     
    In pioneering studies published in the journal Nature Medicine, Department investigators, in collaboration with investigators from Harvard Medical School, demonstrated that antigens delivered in particulate form generate effective cellular immunity against tumors and viruses, leading the way for the development of a novel particle-based immunization strategy currently being evaluated in clinical trials for the treatment of cancer. This technology is currently being developed by by the private sector.. Nature Medicine. 1:649-653. 1995.

    ABSTRACT
     
     
     
     


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