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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.
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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.
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