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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.
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Submitted November 16, 2005
Accepted February 15, 2006
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
Children's Hospital and Regional medical Center, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA
Children's Hospital and Regional medical Center, Seattle, WA, USA
Department of Medicine, University of Washington, Seattle, WA, USA; Puget Sound Blood Center, Seattle, WA, USA
Children's Hospital and Regional medical Center, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA
* Corresponding author; email: miao{at}u.washington.edu.
A robust humoral immune response against human factor FVIII (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/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); combination of CSA and MMF; combination of RAP and MMF; a monoclonal antibody against murine CD40 ligand (MR1); recombinant murine Ctla4Ig; and 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 8/9 animals; the ninth had a transient low titer antibodies. All 9 mice of this group produced persistent, therapeutic levels of hFVIII for >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.
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