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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 (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 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 Matsui, H. Articles by Lillicrap, D. Search for Related Content PubMed PubMed Citation Articles by Matsui, H. Articles by Lillicrap, D. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 12, 2009 Accepted May 6, 2009 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 Matsui, Masaru Shibata, Brian Brown, Andrea Labelle, Carol Hegadorn, Chandler Andrews, Marinee Chuah, Thierry VandenDriessche, Carol H Miao, Christine Hough, and David Lillicrap* Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, University of Leuven, Leuven, Belgium Department of Pediatrics, University of Washington, Seattle, WA, United States * Corresponding author; email: lillicrap{at}cliff.path.queensu.ca. Under certain instances, 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 are essential to develop immune modulating strategies. We have developed a murine model system for studying mechanisms involved in induction of immunological 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 following neonatal gene transfer and tolerance induction is dependant 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 IL-10 and decreased levels of IL-6 and INF. 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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