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 applicatio n of gene therapy for treatment of chronic disorders such as inherited deficiency states. We have found that recombinant adeno-associated vi rus (AAV) efficiently transduces muscle fibers in vivo without activat ion of cellular and humoral immunity to neoantigenic transgene product s such as beta-galactosidase, which differs from the experience with r ecombinant adenovirus, where vibrant T-cell responses to the transgene product destroy the targeted muscle fibers. T cells activated followi ng intramuscular administration of adenovirus expressing lacZ (AdlacZ) can destroy AAVlacZ-transduced muscle fibers, indicating a prior stat e of immunologic nonresponsiveness in the context of AAV gene therapy. Adoptive transfer of dendritic cells infected with AdlacZ leads to im mune mediated elimination of AAVlacZ-transduced muscle fibers. AAVlacZ -transduced antigen-presenting cells fail to demonstrate beta-galactos idase activity and are unable to elicit transgene immunity in adoptive transfer experiments. These studies indicate that vector-mediated tra nsduction of dendritic cells is necessary for cellular immune response s to muscle gene therapy, a step which AAV avoids, providing a useful biological niche for its use in gene therapy.