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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.
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Submitted March 5, 2004
Accepted December 20, 2004
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*
Dept. of Pediatrics, University of Pennsylvania Medical Center and The Children's Hospital of Philadelphia, Philadelphia, PA, USA
* Corresponding author; email: rwherzog{at}mail.med.upenn.edu.
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 hematological disorders. However, an immune response may be initiated if the transgene product represents a neo-antigen. Here, we use ovalbumin (ova) as a model antigen and demonstrate immune-mediated elimination of expression upon 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-MHC II complex 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.
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