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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4677-4684. Prepublished online as a Blood First Edition Paper on February 15, 2005; DOI 10.1182/blood-2004-08-3337. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-08-3337v1 105/12/4677    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dotti, G. Articles by Rooney, C. M. Search for Related Content PubMed PubMed Citation Articles by Dotti, G. Articles by Rooney, C. M. Related Collections Immunobiology Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Human cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis Gianpietro Dotti, Barbara Savoldo, Martin Pule, Karin C. Straathof, Ettore Biagi, Eric Yvon, Stephane Vigouroux, Malcolm K. Brenner, and Cliona M. Rooney From the Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX. Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Faslow and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy. (Blood. 2005;105:4677-4684) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Le Clorennec, T.-S. Ouk, I. Youlyouz-Marfak, S. Panteix, C.-C. Martin, J. Rastelli, E. Adriaenssens, U. Zimber-Strobl, J. Coll, J. Feuillard, et al. Molecular Basis of Cytotoxicity of Epstein-Barr Virus (EBV) Latent Membrane Protein 1 (LMP1) in EBV Latency III B Cells: LMP1 Induces Type II Ligand-Independent Autoactivation of CD95/Fas with Caspase 8-Mediated Apoptosis J. Virol., July 1, 2008; 82(13): 6721 - 6733. [Abstract] [Full Text] [PDF] A. Carbone, A. Gloghini, and G. Dotti EBV-Associated Lymphoproliferative Disorders: Classification and Treatment Oncologist, May 1, 2008; 13(5): 577 - 585. [Abstract] [Full Text] [PDF]

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