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Blood, 15 August 2004, Vol. 104, No. 4, pp. 969-977. Prepublished online as a Blood First Edition Paper on April 22, 2004; DOI 10.1182/blood-2004-03-0847. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-0847v1 104/4/969    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 Dobrzynski, E. Articles by Herzog, R. W. Search for Related Content PubMed PubMed Citation Articles by Dobrzynski, E. Articles by Herzog, R. W. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Immunotherapy Free Research Articles Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Induction of antigen-specific CD4+ T-cell anergy and deletion by in vivo viral gene transfer Eric Dobrzynski, Federico Mingozzi, Yi-Lin Liu, Elisabeth Bendo, Ou Cao, Lixin Wang, and Roland W. Herzog From the Department of Pediatrics, University of Pennsylvania Medical Center, and The Children's Hospital of Philadelphia, Philadelphia, PA. Immune responses to the therapeutic gene product are a potentially serious complication in treatment of genetic disease by gene therapy. Induction and maintenance of immunologic hypo-responsiveness to the therapeutic antigen is therefore critical to the success of gene-based treatment of inherited protein deficiency. Here, we demonstrate induction of antigen-specific CD4+ T-cell tolerance to a secreted transgene product (ovalbumin, ova) in ova-specific T-cell receptor (TCR) transgenic mice by hepatic adeno-associated virus (AAV)–mediated gene transfer. Transduced mice maintained stable circulating ova levels without evidence of an immune response. Lymph node cells and splenocytes were hypo-responsive to ova as early as day 10 after gene transfer. Numbers of TCR+CD4+ cells were reduced in secondary lymphoid organs and in the thymus by 1 to 2 months after vector administration. The remaining TCR+CD4+ cell population was anergic to ova antigen in vitro and enriched for CD25+ cells. These data provide direct evidence that transgene expression following in vivo viral gene transfer can induce CD4+ T-cell tolerance to the transgene product, involving anergy and deletion mechanisms. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Liver gene transfer keeps immune system in check Thierry VandenDriessche Blood 2004 104: 910-911. [Full Text] [PDF] This article has been cited by other articles: J. Lin, Y. Zhi, L. Mays, and J. M. Wilson Vaccines Based on Novel Adeno-Associated Virus Vectors Elicit Aberrant CD8+ T-Cell Responses in Mice J. Virol., November 1, 2007; 81(21): 11840 - 11849. [Abstract] [Full Text] [PDF] F. Mingozzi, N. C. Hasbrouck, E. Basner-Tschakarjan, S. A. Edmonson, D. J. Hui, D. E. Sabatino, S. Zhou, J. F. Wright, H. Jiang, G. F. Pierce, et al. Modulation of tolerance to the transgene product in a nonhuman primate model of AAV-mediated gene transfer to liver Blood, October 1, 2007; 110(7): 2334 - 2341. [Abstract] [Full Text] [PDF] O. Cao, E. Dobrzynski, L. Wang, S. Nayak, B. Mingle, C. Terhorst, and R. W. 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