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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 (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 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. W. Articles by Herzog, R. W. Search for Related Content PubMed PubMed Citation Articles by Cao, O. W. Articles by Herzog, R. W. Related Collections Related Articles in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 8, 2007 Accepted April 12, 2007 Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer Ou W. Cao, Eric Dobrzynski, Lixin Wang, Sushrusha Nayak, Bethany Mingle, Cornelius P. Terhorst, and Roland W. Herzog* Dept. Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Gainesville, FL, United States Dept. Pediatrics, The Children's Hospital of Philadelphia & University of Pennsylvania Medical School, Philadelphia, PA, United States Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States * Corresponding author; email: rherzog{at}ufl.edu. 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 (F.IX) 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+ Treg by in vivo gene transfer. Hepatic gene transfer-induced Treg express FoxP3, GITR, and CTLA4, and suppress CD4+CD25- T cells. Treg are detected as early as two weeks after gene transfer, and increase in frequency in thymus and secondary lymphoid organs during the following two months. Similarly, adoptive lymphocyte transfers from mice tolerized to human F.IX by hepatic AAV gene transfer indicate induction of CD4+CD25+GITR+ that suppress antibody formation to F.IX. Moreover, in vivo depletion of CD4+CD25+ Treg leads to antibody formation to the F.IX 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+ Treg 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: J. Lin, R. Calcedo, L. H. Vandenberghe, P. Bell, S. Somanathan, and J. M. Wilson A New Genetic Vaccine Platform Based on an Adeno-Associated Virus Isolated from a Rhesus Macaque J. Virol., December 15, 2009; 83(24): 12738 - 12750. [Abstract] [Full Text] [PDF] C. H. Miao, B. R. Harmeling, S. F. Ziegler, B. C. Yen, T. Torgerson, L. Chen, R. J. Yau, B. Peng, A. R. Thompson, H. D. Ochs, et al. CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII-specific immune responses in plasmid-mediated gene therapy-treated hemophilia mice Blood, November 5, 2009; 114(19): 4034 - 4044. [Abstract] [Full Text] [PDF] Y. Lu and S. Song Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors PNAS, October 6, 2009; 106(40): 17158 - 17162. [Abstract] [Full Text] [PDF] R. W. 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