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Blood, 12 November 2009, Vol. 114, No. 20, pp. 4373-4382. Prepublished online as a Blood First Edition Paper on September 21, 2009; DOI 10.1182/blood-2009-05-217315. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-05-217315v1 114/20/4373    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 CrossRef Google Scholar Articles by Peng, B. Articles by Miao, C. H. PubMed PubMed Citation Articles by Peng, B. Articles by Miao, C. H. Related Collections Thrombosis and Hemostasis Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Anti-CD3 antibodies modulate anti–factor VIII immune responses in hemophilia A mice after factor VIII plasmid-mediated gene therapy Baowei Peng1, Peiqing Ye1, David J. Rawlings1, Hans D. Ochs1, and Carol H. Miao1 1 Department of Pediatrics, Seattle Children's Research Institute and University of Washington One major obstacle in gene therapy is the generation of immune responses directed against transgene product. Five consecutive anti-CD3 treatments concomitant with factor VIII (FVIII) plasmid injection prevented the formation of inhibitory antibodies against FVIII and achieved persistent, therapeutic levels of FVIII gene expression in treated hemophilia A mice. Repeated plasmid gene transfer is applicable in tolerized mice without eliciting immune responses. Anti-CD3 treatment significantly depleted both CD4+ and CD8+ T cells, whereas increased transforming growth factor-β levels in plasma and the frequency of both CD4+CD25+FoxP3+ and CD4+CD25–Foxp3+ regulatory T cells in the initial few weeks after treatment. Although prior depletion of CD4+CD25+ cells did not abrogate tolerance induction, adoptive transfer of CD4+ cells from tolerized mice at 6 weeks after treatment protected recipient mice from anti-FVIII immune responses. Anti-CD3–treated mice mounted immune responses against both T-dependent and T-independent neo-antigens, indicating that anti-CD3 did not hamper the immune systems in the long term. Concomitant FVIII plasmid + anti-CD3 treatment induced long-term tolerance specific to FVIII via a mechanism involving the increase in transforming growth factor-β levels and the generation of adaptive FVIII-specific CD4+Foxp3+ regulatory T cells at the periphery. Furthermore, anti-CD3 can reduce the titers of preexisting anti-FVIII inhibitory antibodies in hemophilia A mice. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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