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Blood, 16 July 2009, Vol. 114, No. 3, pp. 677-685. Prepublished online as a Blood First Edition Paper on May 20, 2009; DOI 10.1182/blood-2009-03-202267. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2009-03-202267v1 114/3/677    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 Google Scholar Articles by Matsui, H. Articles by Lillicrap, D. PubMed PubMed Citation Articles by Matsui, H. Articles by Lillicrap, D. Related Collections Immunobiology Thrombosis and Hemostasis Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS A murine model for induction of long-term immunologic tolerance to factor VIII does not require persistent detectable levels of plasma factor VIII and involves contributions from Foxp3+ T regulatory cells Hideto Matsui1,*, Masaru Shibata1,2,*, Brian Brown1, Andrea Labelle1, Carol Hegadorn1, Chandler Andrews1, Marinee Chuah3, Thierry VandenDriessche3, Carol H. Miao4, Christine Hough1, and David Lillicrap1 1 Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON; 2 Department of Pediatrics, Nara Medical University, Kashihara, Japan; 3 Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium; and 4 Department of Pediatrics, University of Washington, Seattle Under certain instances, factor VIII (FVIII) stimulates an immune response, and the resulting neutralizing antibodies present a significant clinical challenge. Immunotherapies to re-establish or induce long-term tolerance would be beneficial, and an in-depth knowledge of mechanisms involved in tolerance induction is essential to develop immune-modulating strategies. We have developed a murine model system for studying mechanisms involved in induction of immunologic tolerance to FVIII in hemophilia A mice. We used lentiviral vectors to deliver the canine FVIII transgene to neonatal hemophilic mice and demonstrated that induction of long-term FVIII tolerance could be achieved. Hemophilia A mice are capable of mounting a robust immune response to FVIII after neonatal gene transfer, and tolerance induction is dependent on the route of delivery and type of promoter used. High-level expression of FVIII was not required for tolerance induction and, indeed, tolerance developed in some animals without evidence of detectable plasma FVIII. Tolerance to FVIII could be adoptively transferred to naive hemophilia recipient mice, and FVIII-stimulated splenocytes isolated from tolerized mice expressed increased levels of interleukin-10 and decreased levels of interleukin-6 and interferon-. Finally, induction of FVIII tolerance mediated by this protocol is associated with a FVIII-expandable population of CD4+CD25+Foxp3+ regulatory T cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. W. Scott T regulatory cells turn on T regulatory cells Blood, November 5, 2009; 114(19): 3975 - 3976. [Full Text] [PDF] C. H. Miao, B. R. Harmeling, S. F. Ziegler, B. C. Yen, T. Torgerson, L. Chen, R. J. Yau, B. Peng, A. R. Thompson, H. D. Ochs, et al. CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII-specific immune responses in plasmid-mediated gene therapy-treated hemophilia mice Blood, November 5, 2009; 114(19): 4034 - 4044. [Abstract] [Full Text] [PDF]

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