SEARCH:   Advanced

Blood, 1 July 2006, Vol. 108, No. 1, pp. 19-27. Prepublished online as a Blood First Edition Paper on February 28, 2006; DOI 10.1182/blood-2005-11-4532. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-11-4532v1 108/1/19    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 Miao, C. H. Articles by Ochs, H. D. Search for Related Content PubMed PubMed Citation Articles by Miao, C. H. Articles by Ochs, H. D. Related Collections Hemostasis, Thrombosis, and Vascular Biology Plenary Papers Free Research Articles Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLENARY PAPERS Immunomodulation of transgene responses following naked DNA transfer of human factor VIII into hemophilia A mice Carol H. Miao, Peiqing Ye, Arthur R. Thompson, David J. Rawlings, and Hans D. Ochs From the Children's Hospital and Regional Medical Center, Departments of Pediatrics and Medicine, University of Washington; and Puget Sound Blood Center, Seattle, WA. A robust humoral immune response against human factor VIII (hFVIII) following naked DNA transfer into immunocompetent hemophilia A mice completely inhibits circulating FVIII activity despite initial high-level hFVIII gene expression. To prevent this undesirable response, we compared transient immunomodulation strategies. Eight groups of mice (n = 4-9 per group) were treated with naked DNA transfer of pBS-HCRHPI-hFVIIIA simultaneously with immunosuppressive reagents that included cyclosporine A (CSA), rapamycin (RAP), mycophenylate mofetil (MMF), a combination of CSA and MMF, a combination of RAP and MMF, a monoclonal antibody against murine CD40 ligand (MR1), recombinant murine Ctla4Ig, and a combination of MR1 and Ctla4Ig. All animals except those receiving only CSA exhibited delayed or absent immune responses against hFVIII. The most effective immunosuppressive regimen, the combination of Ctla4Ig and MR1, prevented inhibitor formation in 8 of 9 animals; the ninth had transient low-titer antibodies. All 9 mice of this group produced persistent, therapeutic levels of hFVIII for more than 6 months. When challenged with the T-dependent antigen bacteriophage x174, tolerized mice exhibited normal primary and secondary antibody responses, suggesting that transient immunomodulation to disrupt B/T-cell interaction at the time of plasmid injection effectively promoted long-term immune tolerance specific for hFVIII. (Blood. 2006;108:19-27) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: When gene therapy marries immunology: an important vow David W. Scott Blood 2006 108: 2-3. [Full Text] [PDF] This article has been cited by other articles: L. M. Ide, B. Gangadharan, K.-Y. Chiang, C. B. Doering, and H. T. Spencer Hematopoietic stem-cell gene therapy of hemophilia A incorporating a porcine factor VIII transgene and nonmyeloablative conditioning regimens Blood, October 15, 2007; 110(8): 2855 - 2863. [Abstract] [Full Text] [PDF]

	Copyright © 2006 by American Society of Hematology         Online ISSN: 1528-0020