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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1662-1672. Prepublished online as a Blood First Edition Paper on June 23, 2008; DOI 10.1182/blood-2008-01-128413. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-01-128413v1 112/5/1662    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 Citing Articles via Google Scholar Google Scholar Articles by Peng, B. Articles by Miao, C. H. Search for Related Content PubMed PubMed Citation Articles by Peng, B. Articles by Miao, C. H. Related Collections Hemostasis, Thrombosis, and Vascular Biology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice Baowei Peng1, Peiqing Ye1, Bruce R. Blazar2, Gordon J. Freeman3, David J. Rawlings1, Hans D. Ochs1, and Carol H. Miao1 1 Department of Pediatrics, Seattle Children's Hospital Research Institute and University of Washington, Seattle; 2 Department of Pediatrics, Division of Blood and Marrow Transplantation, and the Cancer Center, University of Minnesota, Minneapolis; and 3 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid–treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS+CD4+ T cells and activation of CD25+Foxp3+ Tregs in the peripheral blood, spleen, and lymph nodes. CD4+ T cells from anti-ICOS–treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-β. Moreover, CD4+CD25+ Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS–treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage x 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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