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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4226-4234. Prepublished online as a Blood First Edition Paper on February 15, 2005; DOI 10.1182/blood-2004-03-0848. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-0848v1 105/11/4226    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 Wang, L. Articles by Herzog, R. W. Search for Related Content PubMed PubMed Citation Articles by Wang, L. Articles by Herzog, R. W. Related Collections Immunobiology Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Systemic protein delivery by muscle-gene transfer is limited by a local immune response Lixin Wang, Eric Dobrzynski, Alexander Schlachterman, Ou Cao, and Roland W. Herzog From the Department of Pediatrics, University of Pennsylvania Medical Center and Children's Hospital of Philadelphia, Philadelphia, PA. Adeno-associated viral (AAV) vectors have been successfully used for therapeutic expression of systemic transgene products (such as factor IX or erythropoietin) following in vivo administration to skeletal muscle of animal models of inherited hematologic disorders. However, an immune response may be initiated if the transgene product represents a neoantigen. Here, we use ovalbumin (OVA) as a model antigen and demonstrate immune-mediated elimination of expression on muscle-directed AAV-2 gene transfer. Administration to immune competent mice resulted in transient systemic OVA expression. Within 10 days, OVA-specific T-helper cells had been activated in draining lymph nodes, an inflammatory immune response ensued, and OVA-expressing muscle fibers were destroyed by a cytotoxic CD8+ T-cell response. Use of a muscle-specific promoter did not prevent this immune response. Adoptively transferred CD4+ cells transgenic for a T-cell receptor specific to OVA peptide-major histocompatibility complex class II showed antigen-specific, vector dose-dependent proliferation confined to the draining lymph nodes of AAV-OVA–transduced muscle within 5 days after gene transfer and subsequently participated in lymphocytic infiltration of transduced muscle. This study documents that a local immune response limits sustained expression of a secreted protein in muscle gene transfer, a finding that may have consequences for design of clinical protocols. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. N. Radcliffe, J. S. Roddick, F. K. Stevenson, and S. M. Thirdborough Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development J. Immunol., December 15, 2007; 179(12): 8313 - 8321. [Abstract] [Full Text] [PDF] J. Lin, Y. Zhi, L. Mays, and J. M. Wilson Vaccines Based on Novel Adeno-Associated Virus Vectors Elicit Aberrant CD8+ T-Cell Responses in Mice J. Virol., November 1, 2007; 81(21): 11840 - 11849. [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] E. Dobrzynski, J. C. Fitzgerald, O. Cao, F. Mingozzi, L. Wang, and R. W. Herzog Prevention of cytotoxic T lymphocyte responses to factor IX-expressing hepatocytes by gene transfer-induced regulatory T cells PNAS, March 21, 2006; 103(12): 4592 - 4597. [Abstract] [Full Text] [PDF]

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