Research Program:

Our laboratory is interested in using Fas (CD95) ligand as an immunosuppressive agent to prevent transplant rejection, treat autoimmune disease and kill certain cancers. The basis for this is as follows. In brief, activated, antigen-specific T cells and some tumor cells express the Fas receptor (FasR). Upon cross-linking of FasR with agonistic anti-Fas antibody or with Fas ligand (FasL), the cells undergo apoptosis and die. We are using mammalian expression plasmids as well as recombinant adenovirus and retrovirus encoding FasL to transfect/transduce cells and organs prior to transplantation. This technology is also being applied in an exploratory manner to kill a variety of human tumor cells growing in immunocompromised scid and nude mice.

Our lab also studies a novel vaccine delivery system discovered in collaboration with Dr. Alex Franzusoff (UCHSC). This vaccine, which comprises recombinant Saccharomyces cerevisiae expressing the HIV gp160 envelope protein, has been extensively tested for immunogenicity in mice and pig-tailed macaques. It is currently being tested for efficacy in a tumor cell model.

Selected References:

• Bellgrau, D., Gold, D., Selawry, H., Moore, J., Franzusoff, A., and Duke, R.C. 1995. A role for CD95 ligand in preventing graft rejection. Nature 377:631-634. Duke, R.C., Franzusoff, A. and Bellgrau, D. 1996. CD95 ligand in graft rejection. Nature 379:682-683.
• Duke, R.C., Ojcius, D., and Young, J.D.-E. 1996. Death of a cell. Sci. Am. 275:80-87.
• Nash, P.B., Purner, M.B., Leon, R.P., Clarke, P., Duke, R.C. and Curiel, T.J. 1998. Toxoplasma gondii infected cells are resistant to multiple inducers of apoptosis. J. Immunol. 160:1824-1830.
• Hedlund, T.E., Duke, R.C., Schleicher, M.S. and Miller, G.J. 1998. Fas-mediated apoptosis in seven human prostate cancer cell lines: correlation with tumor stage. Prostate 36:92-101.
• Leon, R., Hedlund, T., Meech, S.J., Li, S., Schaack, J., Hunger, S., Duke, R., and DeGregori, J. 1998. Adenoviral mediated gene transfer in lymphocytes. Proc. Natl. Acad. Sci. USA 95:13159-13164.
• Desbarats, J., Duke, R.C. and Newell, M.K. 1998. Novel role of Fas ligand in cell cycle arrest of CD4 T cells. Nature Med. 4:in press.
• Duke, R.C., Newell, E., Schleicher, M., Meech, S., and Bellgrau, D. 1998. Transplantation of cells and tissues expressing Fas ligand. Transplant Proc. (in press).
• Hedlund, T.E., Schaack, J.B., Meech, S.J., Srikanth, S., Kraft, A.S., Miller, G.J. and Duke, R.C. 1999. Adenovirus-mediated expression of Fas ligand induces apoptosis of human prostate cancer cells. Cell Death Differ. (in press).
• Stubbs, A., Bellgrau, D., Franzusoff, A., Moore, J. and Duke, R.C. 1999. Recombinant HIV yeast-based vaccine delivers antigen via MHC-I and II, stimulating cellular and humoral responses in mice. J. Biol. Chem (in press).

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