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Blood, 15 July 2006, Vol. 108, No. 2, pp. 480-486. Prepublished online as a Blood First Edition Paper on March 16, 2006; DOI 10.1182/blood-2005-11-4668. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-11-4668v1 108/2/480    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 Gene Therapy Hemostasis, Thrombosis, and Vascular Biology Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Immune deviation by mucosal antigen administration suppresses gene-transfer–induced inhibitor formation to factor IX Ou Cao, Elina Armstrong, Alexander Schlachterman, Lixin Wang, David K. Okita, Bianca Conti-Fine, Katherine A. High, and Roland W. Herzog From the Department of Pediatrics, Division of Cellular and Molecular Therapy, University of Florida, Alachua; Department of Pediatrics, The Children's Hospital of Philadelphia and University of Pennsylvania Medical School, Philadelphia; Department of Biochemistry, University of Minnesota, Minneapolis; and Howard Hughes Medical Institute, Chevy Chase, MD. Formation of inhibitory antibodies is a serious complication of protein or gene replacement therapy for hemophilias, congenital X-linked bleeding disorders. In hemophilia B (coagulation factor IX [F.IX] deficiency), lack of endogenous F.IX antigen expression and other genetic factors may increase the risk of antibody formation to functional F.IX. Here, we developed a protocol for reducing inhibitor formation in gene therapy by prior mucosal (intranasal) administration of a peptide representing a human F.IX-specific CD4+ T-cell epitope in hemophilia B mice. C3H/HeJ mice with a F.IX gene deletion produced inhibitory IgG to human F.IX after hepatic gene transfer with an adeno-associated viral vector. These animals subsequently lost systemic F.IX expression. In contrast, repeated intranasal administration of the specific peptide resulted in reduced inhibitor formation, sustained circulating F.IX levels, and sustained partial correction of coagulation following hepatic gene transfer. This was achieved through immune deviation to a T-helper–cell response with increased IL-10 and TGF- production and activation of regulatory CD4+CD25+ T cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: O. Cao, E. Dobrzynski, L. Wang, S. Nayak, B. Mingle, C. Terhorst, and R. W. Herzog Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer Blood, August 15, 2007; 110(4): 1132 - 1140. [Abstract] [Full Text] [PDF]

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