 |
 |
 |
 |
 |
 |
 |
Member Information
James Riley, PhD
Department of Pathology and Laboratory Medicine
Office Phone: 215-573-6792
Office Fax:
Email:
Website(s): http://www.uphs.upenn.edu/path/residency/faculty.html
Education:
Keywords: HIV pathogenesis and Immunotherapy
Research and/or Clinical Interests:
Identifying the role T cell activation plays in susceptibility to HIV infection and development of culture systems to expand HIV infected T cells for adoptive transfer clinical trials.
Summary:
Ex vivo expansion and infusion of polyclonal and antigen-specific T cells into HIV-infected individuals holds great promise to prevent opportunistic infections and bolster immunological control of HIV infection. However, since T cells are targets of HIV infection and T cells isolated from HIV-infected individuals are defective in their response to mitogens, difficulties have been encountered obtaining sufficient T cells for use in immunotherapy. Anti-CD3 and anti-CD28 (CD3/28) coated beads were the first generation of artificial APCs (aAPC) that permitted the expansion of HIV-infected T cells. In addition to delivering the signals needed for T cell activation and growth, CD3/28 bead stimulation renders T cells resistant to R5 infection by downregulating CCR5 and upregulating the expression of its ligands, the ?-chemokines RANTES, MIP-1?? and MIP-1?. Several phase I and II trials have demonstrated that infusion of up to 3 x10 10 autologous CD4 T cells into R5-infected individuals expanded using CD3/28 coated beads is both safe and feasible. More importantly, sustained increases in the total lymphocyte count, the CD4-to-CD8 T cell ratio, fraction of cytokine-secreting T cells, and the ability to respond to recall antigens was observed, suggesting that adoptive transfer of T cells has the potential to restore at least limited immune function back to HIV infected individuals. Despite the success of these initial trials, several limitations were noted, including the difficulty of (1) expanding CD8 T cells, (2) adding additional costimulatory signals that may be required to expand certain subsets of T cells, (3) removing the beads before infusion and (4) generating antigen specific T cells with a high engraftment potential. My lab in collaboration with Dr. Carl June's laboratory have recently developed a cell-based aAPC that we postulate will overcome many of these limitations. Using lentiviral vectors to stably add costimulatory molecules to these aAPCs, we will determine which combination of costimulatory signals will optimally expand both CD4 and CD8 T cells from HIV-infected individuals. We predict that these studies will enable the expansion of distinct T cell subsets that have unique abilities to reconstitute immune function in HIV infected individuals. While infusion of polyclonal T cells will be helpful to prevent immunodeficiency, it is likely to have only a modest effect on the ability of the immune system to rid itself of HIV. Thus, we are currently developing strategies to expand HIV-specific T cells to therapeutic levels. We hypothesize that the use of chemically inactivated patient virus loaded onto MHC expressing aAPCs will permit the expansion of T cells with a broad specificity that will effectively target the patient's own virus. These ex vivo generated T cells may act as a therapeutic vaccine and effectively control HIV replication in the host. These preclinical studies will form the basis and rationale for future clinical trials that will test the hypothesis that immune function can be restored in HIV-1 infected individuals by adoptive transfer of polyclonal and HIV specific T cells.
Representative Publications:
Parry,R.V., Rumbley , C.A. , Vandenberghe,L.H., June,C.H., & Riley,J.L. CD28 and inducible costimulatory protein Src homology 2 binding domains show distinct regulation of phosphatidylinositol 3-kinase, Bcl-x(L), and IL-2 expression in primary human CD4 T lymphocytes. J. Immunol. 171, 166-174 (2003).
Simmons,G., Reeves,J.D., Grogan,C.C., Vandenberghe,L.H., Baribaud,F., Whitbeck,J.C., Burke,E., Buchmeier,M.J., Soilleux,E.J., Riley,J.L., Doms,R.W., Bates,P., & Pohlmann,S. DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology 305, 115-123 (2003).
Thomas,A.K., Maus,M.V., Shalaby,W.S., June,C.H., & Riley,J.L. A cell-based artificial antigen-presenting cell coated with anti-CD3 and CD28 antibodies enables rapid expansion and long-term growth of CD4 T lymphocytes. Clin. Immunol. 105, 259-272 (2002).
Riley,J.L., Mao,M., Kobayashi,S., Biery,M., Burchard,J., Cavet,G., Gregson,B.P., June,C.H., & Linsley,P.S. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc. Natl. Acad. Sci. U. S. A 99, 11790-11795 (2002).
Frauwirth,K.A., Riley,J.L., Harris,M.H., Parry,R.V., Rathmell,J.C., Plas,D.R., Elstrom,R.L., June,C.H., & Thompson,C.B. The CD28 signaling pathway regulates glucose metabolism. Immunity. 16, 769-777 (2002).
Maus,M.V., Thomas,A.K., Leonard,D.G., Allman,D., Addya,K., Schlienger,K., Riley,J.L., & June,C.H. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Nat. Biotechnol. 20, 143-148 (2002).
Riley,J.L., Schlienger,K., Blair,P.J., Carreno,B., Craighead,N., Kim,D., Carroll,R.G., & June,C.H. Modulation of susceptibility to HIV-1 infection by the cytotoxic T lymphocyte antigen 4 costimulatory molecule. J. Exp. Med. 191, 1987-1997 (2000).
Xiao,X., Wu,L., Stantchev,T.S., Feng,Y.R., Ugolini,S., Chen,H., Shen,Z., Riley,J.L., Broder,C.C., Sattentau,Q.J., & Dimitrov,D.S. Constitutive cell surface association between CD4 and CCR5. Proc. Natl. Acad. Sci. U. S. A 96, 7496-7501 (1999).
Riley,J.L., Levine,B.L., Craighead,N., Francomano,T., Kim,D., Carroll,R.G., & June,C.H. Naive and memory CD4 T cells differ in their susceptibilities to human immunodeficiency virus type 1 infection following CD28 costimulation: implicatip6s for transmission and pathogenesis. J. Virol. 72, 8273-8280 (1998).
Yang,L.P., Riley,J.L., Carroll,R.G., June,C.H., Hoxie,J., Patterson,B.K., Ohshima,Y., Hodes,R.J., & Delespesse,G. Productive infection of neonatal CD8+ T lymphocytes by HIV-1. J. Exp. Med. 187, 1139-1144 (1998).
Riley,J.L., Carroll,R.G., Levine,B.L., Bernstein,W., St Louis,D.C., Weislow,O.S., & June,C.H. Intrinsic resistance to T cell infection with HIV type 1 induced by CD28 costimulation. J. Immunol. 158, 5545-5553 (1997).
Carroll,R.G., Riley,J.L., Levine,B.L., Feng,Y., Kaushal,S., Ritchey,D.W., Bernstein,W., Weislow,O.S., Brown,C.R., Berger,E.A., June,C.H., & St Louis,D.C. Differential regulation of HIV-1 fusion cofactor expression by CD28 costimulation of CD4+ T cells. Science 276, 273-276 (1997).
Levine,B.L., Mosca,J.D., Riley,J.L., Carroll,R.G., Vahey,M.T., Jagodzinski,L.L., Wagner,K.F., Mayers,D.L., Burke,D.S., Weislow,O.S., St Louis,D.C., & June,C.H. Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 costimulation. Science 272, 1939-1943 (1996).
