Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Jooss, K; Yang, Y; Fisher, KJ; Wilson, JM

Published Date

  • May 1998

Published In

Volume / Issue

  • 72 / 5

Start / End Page

  • 4212 - 4223

PubMed ID

  • 9557710

Pubmed Central ID

  • 9557710

International Standard Serial Number (ISSN)

  • 0022-538X

Language

  • eng

Conference Location

  • United States