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Blood, 15 August 2007, Vol. 110, No. 4, pp. 1132-1140. Prepublished online as a Blood First Edition Paper on April 16, 2007; DOI 10.1182/blood-2007-02-073304. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-02-073304v1 110/4/1132    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 Cao, O. Articles by Herzog, R. W. Search for Related Content PubMed PubMed Citation Articles by Cao, O. Articles by Herzog, R. W. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Therapy Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer Ou Cao1, Eric Dobrzynski2, Lixin Wang1, Sushrusha Nayak1, Bethany Mingle2, Cox Terhorst3, and Roland W. Herzog1 1 Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville; 2 Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Medical School, Philadelphia; 3 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Gene replacement therapy is complicated by the risk of an immune response against the therapeutic transgene product, which in part is determined by the route of vector administration. Our previous studies demonstrated induction of immune tolerance to coagulation factor IX (FIX) by hepatic adeno-associated viral (AAV) gene transfer. Using a regulatory T-cell (Treg)–deficient model (Rag-2–/– mice transgenic for ovalbumin-specific T-cell receptor DO11.10), we provide first definitive evidence for induction of transgene product-specific CD4+CD25+ Tregs by in vivo gene transfer. Hepatic gene transfer–induced Tregs express FoxP3, GITR, and CTLA4, and suppress CD4+CD25– T cells. Tregs are detected as early as 2 weeks after gene transfer, and increase in frequency in thymus and secondary lymphoid organs during the following 2 months. Similarly, adoptive lymphocyte transfers from mice tolerized to human FIX by hepatic AAV gene transfer indicate induction of CD4+CD25+GITR+ that suppresses antibody formation to FIX. Moreover, in vivo depletion of CD4+CD25+ Tregs leads to antibody formation to the FIX transgene product after hepatic gene transfer, which strongly suggests that these regulatory cells are required for tolerance induction. Our study reveals a crucial role of CD4+CD25+ Tregs in preventing immune responses to the transgene product in gene transfer. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Articles in Blood Online: TLR3 signaling does not affect organ-specific immune responses to factor IX in AAV gene therapy Ou Cao and Roland W. Herzog Blood 2008 112: 910-911. [Full Text] [PDF] Critical importance of the cell system when studying tissue factor de-encryption Hai Po Helena Liang and Philip J. Hogg Blood 2008 112: 912-913. [Full Text] [PDF] Inducing Tregs with hepatic gene therapy David Lillicrap Blood 2007 110: 1089. [Full Text] [PDF] This article has been cited by other articles: L. E. Mays, L. H. Vandenberghe, R. Xiao, P. Bell, H.-J. Nam, M. Agbandje-McKenna, and J. M. Wilson Adeno-Associated Virus Capsid Structure Drives CD4-Dependent CD8+ T Cell Response to Vector Encoded Proteins J. Immunol., May 15, 2009; 182(10): 6051 - 6060. [Abstract] [Full Text] [PDF] G. P. Niemeyer, R. W. Herzog, J. Mount, V. R. Arruda, D. M. Tillson, J. Hathcock, F. W. van Ginkel, K. A. High, and C. D. Lothrop Jr Long-term correction of inhibitor-prone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy Blood, January 22, 2009; 113(4): 797 - 806. [Abstract] [Full Text] [PDF] B. Waters, M. Qadura, E. Burnett, R. Chegeni, A. Labelle, P. Thompson, C. Hough, and D. Lillicrap Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response Blood, January 1, 2009; 113(1): 193 - 203. [Abstract] [Full Text] [PDF] S. Sehrawat, S. Suvas, P. P. Sarangi, A. Suryawanshi, and B. T. Rouse In Vitro-Generated Antigen-Specific CD4+ CD25+ Foxp3+ Regulatory T Cells Control the Severity of Herpes Simplex Virus-Induced Ocular Immunoinflammatory Lesions J. Virol., July 15, 2008; 82(14): 6838 - 6851. [Abstract] [Full Text] [PDF] 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]

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