Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers.
Immune responses to vector-corrected cells have limited the application of gene therapy for treatment of chronic disorders such as inherited deficiency states. We have found that recombinant adeno-associated virus (AAV) efficiently transduces muscle fibers in vivo without activation of cellular and humoral immunity to neoantigenic transgene products such as beta-galactosidase, which differs from the experience with recombinant adenovirus, where vibrant T-cell responses to the transgene product destroy the targeted muscle fibers. T cells activated following intramuscular administration of adenovirus expressing lacZ (AdlacZ) can destroy AAVlacZ-transduced muscle fibers, indicating a prior state of immunologic nonresponsiveness in the context of AAV gene therapy. Adoptive transfer of dendritic cells infected with AdlacZ leads to immune mediated elimination of AAVlacZ-transduced muscle fibers. AAVlacZ-transduced antigen-presenting cells fail to demonstrate beta-galactosidase activity and are unable to elicit transgene immunity in adoptive transfer experiments. These studies indicate that vector-mediated transduction of dendritic cells is necessary for cellular immune responses to muscle gene therapy, a step which AAV avoids, providing a useful biological niche for its use in gene therapy.
Jooss
K
K
Institute for Human Gene Therapy and Department of Medicine, University of Pennsylvania Health System, and The Wistar Institute, Philadelphia 19104, USA.
Yang
Y
Y
Fisher
K J
KJ
Wilson
J M
JM
D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002472:Cell Transformation, Viral; D003713:Dendritic Cells / Q000276:immunology*; D000229:Dependovirus / Q000276:immunology*; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019076:Transgenes; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology
D001616:beta-Galactosidase