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Blood, 15 January 2009, Vol. 113, No. 3, pp. 538-545. Prepublished online as a Blood First Edition Paper on June 19, 2008; DOI 10.1182/blood-2008-01-131375. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2008-01-131375v1 113/3/538    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 Velazquez, V. M. Articles by Walker, C. M. Search for Related Content PubMed PubMed Citation Articles by Velazquez, V. M. Articles by Walker, C. M. Related Collections Immunobiology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector–mediated gene therapy Victoria M. Velazquez1, David G. Bowen1, and Christopher M. Walker1,2 1 The Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio; and 2 Department of Pediatrics, College of Medicine, The Ohio State University, Columbus Recombinant adeno-associated virus (rAAV) vectors are considered promising for human gene replacement because they facilitate stable expression of therapeutic proteins in transduced tissues. Whether the success of gene therapy will be influenced by cellular immune responses targeting transgene-encoded proteins that are potentially immunogenic is unknown. Here we characterized CD8+ T-cell activity against β-galactosidase and enhanced green fluorescent protein, model antigens containing major histocompatibility complex (MHC) class I epitopes that are constitutively produced in murine skeletal muscle after rAAV vector transduction. Antigen-specific CD8+ T cells were detected in the spleen and liver of mice within 7 days of muscle transduction. CD8+ T-cell frequencies in these organs were stable, and effector functions were intact for months despite ongoing antigen production in muscle. CD8+ T cells also infiltrated transduced muscle, where frequencies were at least 5-fold higher than in untransduced spleen and liver. Significantly, the majority of antigen-specific CD8+ T cells in vector-transduced muscle were not functional. Loss of function in the muscle was associated with programmed death of the effector cells. Stable gene expression therefore depended on selective death of CD8+ T cells at the site of antigen production, an effective mechanism for subverting immunity that is also potentially reversible. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Mingozzi, J. J. Meulenberg, D. J. Hui, E. Basner-Tschakarjan, N. C. Hasbrouck, S. A. Edmonson, N. A. Hutnick, M. R. Betts, J. J. Kastelein, E. S. Stroes, et al. AAV-1-mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells Blood, September 3, 2009; 114(10): 2077 - 2086. [Abstract] [Full Text] [PDF] C. Li, M. Hirsch, N. DiPrimio, A. Asokan, K. Goudy, R. Tisch, and R. J. Samulski Cytotoxic-T-Lymphocyte-Mediated Elimination of Target Cells Transduced with Engineered Adeno-Associated Virus Type 2 Vector In Vivo J. Virol., July 1, 2009; 83(13): 6817 - 6824. [Abstract] [Full Text] [PDF]

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