SEARCH:   Advanced

Blood, 5 November 2009, Vol. 114, No. 19, pp. 4034-4044. Prepublished online as a Blood First Edition Paper on August 27, 2009; DOI 10.1182/blood-2009-06-228155. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2009-06-228155v1 114/19/4034    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 Miao, C. H. Articles by Rawlings, D. J. PubMed PubMed Citation Articles by Miao, C. H. Articles by Rawlings, D. J. Related Collections Thrombosis and Hemostasis Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII–specific immune responses in plasmid-mediated gene therapy–treated hemophilia mice Carol H. Miao1,2, Benjamin R. Harmeling1, Steven F. Ziegler3, Benjamin C. Yen1, Troy Torgerson1,2, Liping Chen1, Roger J. Yau1, Baowei Peng1, Arthur R. Thompson4, Hans D. Ochs1,2, and David J. Rawlings1,2 1 Seattle Children's Research Institute, WA; 2 Department of Pediatrics, University of Washington, Seattle; 3 Immunology, Benaroya Research Institute, Seattle, WA; and 4 Puget Sound Blood Center, Seattle, WA Gene transfer of a factor VIII (FVIII) plasmid into hemophilia A (HemA) mice achieved supraphysiologic FVIII expression, but triggered production of high-titer FVIII-specific antibodies and loss of functional FVIII activity. To test whether FVIII-specific regulatory T cells (Tregs) can modulate immune responses against FVIII, we developed a HemA mouse model in which all T cells overexpressed Foxp3 (HemA/Foxp3-Tg). FVIII plasmid therapy did not induce antibody production in HemA/Foxp3-Tg mice. CD4+Foxp3+ T cells isolated from plasmid-treated HemA/Foxp3-Tg mice significantly suppressed proliferation of FVIII-stimulated CD4+ effector T cells. The percentage of CD4+ T cells expressing CD25, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4 increased significantly in spleen and peripheral blood for 9 weeks. Mice receiving adoptively transferred Tregs from FVIII-exposed HemA/Foxp3-Tg mice produced significantly reduced antibody titers compared with controls after initial challenge with FVIII plasmid and second challenge 16 weeks after first plasmid treatment. Adoptively transferred Tregs engrafted and distributed at 2% to 4% in the Treg compartment of blood, lymph nodes, and spleens of the recipient mice and induced activation of endogenous Tregs; the engraftment decreased to negligible levels over 8 to 12 weeks. Antigen-specific Tregs can provide long-lasting protection against immune responses in vivo and limit recall responses induced by a second challenge via infectious tolerance. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: T regulatory cells turn on T regulatory cells David W. Scott Blood 2009 114: 3975-3976. [Full Text] [PDF] 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]

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020