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Blood, 15 August 2004, Vol. 104, No. 4, pp. 969-977.
Prepublished online as a Blood First Edition Paper on April 22, 2004; DOI 10.1182/blood-2004-03-0847.
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Submitted March 5, 2004
Accepted April 5, 2004
Induction of Antigen-specific CD4+ T Cell Anergy and Deletion by In Vivo Viral Gene Transfer
Eric Dobrzynski, Federico Mingozzi, Yi-Lin Liu, Elisabeth Bendo, Ou Cao, Lixin Wang, and Roland W Herzog*
Pediatrics, University of Pennsylvania Medical Center and The Childrens Hospital of Philadelphia, Philadelphia, PA, USA
* Corresponding author; email: rwherzog{at}mail.med.upenn.edu.
Immune responses to the therapeutic gene product are a potentially serious complication in treatment of genetic disease by gene therapy. Induction and maintenance of immunological hypo-responsiveness to the therapeutic antigen is therefore critical to the success of gene-based treatment of inherited protein deficiency. Here, we demonstrate induction of antigen-specific CD4+ T cell tolerance to a secreted transgene product (ovalbumin, ova) in ova-specific T cell receptor (TCR) transgenic mice by hepatic adeno-associated virus (AAV)-mediated gene transfer. Transduced mice maintained stable circulating ova levels without evidence of an immune response. Lymph node cells and splenocytes were hypo-responsive to ova as early as day 10 post gene transfer. Numbers of TCR+CD4+ cells were reduced in secondary lymphoid organs and in the thymus by 1-2 months after vector administration. The remaining TCR+CD4+ cell population was anergic to ova antigen in vitro and enriched for CD25+ cells. These data provide direct evidence that transgene expression following in vivo viral gene transfer can induce CD4+ T cell tolerance to the transgene product, involving anergy and deletion mechanisms.
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