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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4865-4870. Prepublished online as a Blood First Edition Paper on March 15, 2005; DOI 10.1182/blood-2004-11-4274. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-11-4274v1 105/12/4865    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 Citing Articles via Google Scholar Google Scholar Articles by Lei, T. C. Articles by Scott, D. W. Search for Related Content PubMed PubMed Citation Articles by Lei, T. C. Articles by Scott, D. W. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Transfusion Medicine Immunotherapy Gene Therapy Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSFUSION MEDICINE Induction of tolerance to factor VIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B cells as Ig fusion proteins Tie Chi Lei, and David W. Scott From the Departments of Surgery and of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD. Up to 30% of patients with hemophilia A given therapeutic factor VIII (fVIII) can make inhibitory antibodies, the majority of which are reactive with its C2 and A2 domains. We have previously demonstrated that antigen-specific tolerance to several antigens can be induced by lipopolysaccharide (LPS)-activated B-cell blasts transduced with immunoglobulin (IgG)-antigen fusion constructs. To apply this system to hemophilia A inhibitor formation, we created retroviral vectors expressing fVIII amino acids S2173-Y2332 (C2 domain) and S373-R740 (A2 domain) in frame with an IgG heavy chain backbone. These vectors were transduced into B-cell blasts to induce tolerance in both naive and fVIII-primed hemophilic (E16 fVIII-/-) mice. Thus, treatment of E16 fVIII-/- mice with B cells expressing fVIII C2 and A2 domains led to tolerance in terms of specific humoral response (including inhibitory antibody titers) and cellular responses to fVIII and its C2 or A2 domains. Moreover, a significant reduction in immune responses to fVIII could be achieved in immunized hemophilic mice with existing anti-fVIII titers. This hyporesponsive state persisted for at least 2 months and withstood additional challenge with fVIII. Further experiments, in which mice were treated with a depleting monoclonal anti-CD25, suggested that a regulatory T cell may be required for the tolerogenic effect of transduced B cells. These findings demonstrate that B-cell presentation of fVIII domains on an Ig backbone specifically prevents or decreases existing antibodies in hemophilia A mice. (Blood. 2005;105:4865-4870) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Tolerance induction: a job for B cells? Jean-Marie R. Saint-Remy and Marc G. Jacquemin Blood 2005 105: 4551. [Full Text] [PDF] This article has been cited by other articles: J. Skupsky, A.-H. Zhang, Y. Su, and D. W. Scott A role for thrombin in the initiation of the immune response to therapeutic factor VIII Blood, November 19, 2009; 114(21): 4741 - 4748. [Abstract] [Full Text] [PDF] D. W. Scott T regulatory cells turn on T regulatory cells Blood, November 5, 2009; 114(19): 3975 - 3976. [Full Text] [PDF] H. Matsui, M. Shibata, B. Brown, A. Labelle, C. Hegadorn, C. Andrews, M. Chuah, T. VandenDriessche, C. H. Miao, C. Hough, et al. 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 Blood, July 16, 2009; 114(3): 677 - 685. [Abstract] [Full Text] [PDF] B. Waters, M. Qadura, E. Burnett, R. Chegeni, A. Labelle, P. Thompson, C. Hough, and D. Lillicrap Anti-CD3 prevents factor VIII inhibitor development in hemophilia A mice by a regulatory CD4+CD25+-dependent mechanism and by shifting cytokine production to favor a Th1 response Blood, January 1, 2009; 113(1): 193 - 203. [Abstract] [Full Text] [PDF] D. W. Scott, E. Kadavil, A.-H. Zhang, R. A. Ettinger, and K. Pratt Induction of 'Tolerance' in a T-Cell Clone from a Mild Hemophilia Patient Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 3526 - 3526. [Abstract] F. Frommer, T. J. A. J. Heinen, F. T. Wunderlich, N. Yogev, T. Buch, A. Roers, E. Bettelli, W. Muller, S. M. Anderton, and A. Waisman Tolerance without Clonal Expansion: Self-Antigen-Expressing B Cells Program Self-Reactive T Cells for Future Deletion J. Immunol., October 15, 2008; 181(8): 5748 - 5759. [Abstract] [Full Text] [PDF] A. S. De Groot, L. Moise, J. A. McMurry, E. Wambre, L. Van Overtvelt, P. Moingeon, D. W. Scott, and W. Martin Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes" Blood, October 15, 2008; 112(8): 3303 - 3311. [Abstract] [Full Text] [PDF] B. Peng, P. Ye, B. R. Blazar, G. J. Freeman, D. J. Rawlings, H. D. Ochs, and C. H. Miao Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice Blood, September 1, 2008; 112(5): 1662 - 1672. [Abstract] [Full Text] [PDF] Y. Su, G. Carey, M. Maric, and D. W. Scott B Cells Induce Tolerance by Presenting Endogenous Peptide-IgG on MHC Class II Molecules via an IFN-{gamma}-Inducible Lysosomal Thiol Reductase-Dependent Pathway J. Immunol., July 15, 2008; 181(2): 1153 - 1160. [Abstract] [Full Text] [PDF] S. Lacroix-Desmazes, A.-M. Navarrete, S. Andre, J. Bayry, S. V. Kaveri, and S. Dasgupta Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A Blood, July 15, 2008; 112(2): 240 - 249. [Abstract] [Full Text] [PDF] P. Reichardt, B. Dornbach, S. Rong, S. Beissert, F. Gueler, K. Loser, and M. Gunzer Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse Blood, September 1, 2007; 110(5): 1519 - 1529. [Abstract] [Full Text] [PDF] O. Cao, E. Dobrzynski, L. Wang, S. Nayak, B. Mingle, C. Terhorst, and R. W. Herzog Induction and role of regulatory CD4+CD25+ T cells in tolerance to the transgene product following hepatic in vivo gene transfer Blood, August 15, 2007; 110(4): 1132 - 1140. [Abstract] [Full Text] [PDF] O. Cao, E. Armstrong, A. Schlachterman, L. Wang, D. K. Okita, B. Conti-Fine, K. A. High, and R. W. Herzog Immune deviation by mucosal antigen administration suppresses gene-transfer-induced inhibitor formation to factor IX Blood, July 15, 2006; 108(2): 480 - 486. [Abstract] [Full Text] [PDF] M. T. Litzinger, Y. Su, T. C. Lei, N. Soukhareva, and D. W. Scott Mechanisms of Gene Therapy for Tolerance: B7 Signaling Is Required for Peptide-IgG Gene-Transferred Tolerance Induction J. Immunol., July 15, 2005; 175(2): 780 - 787. [Abstract] [Full Text] [PDF]

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