title: The role of apoptosis in immune hyporesponsiveness following AAV8 liver gene transfer.
abstract: Gene therapy provides a significant opportunity to treat a variety of inherited and acquired diseases. However, adverse immune responses toward the adeno-associated virus (AAV) antigens may limit its success. The mechanisms responsible for immunity or tolerance toward AAV-encoded transgene products remain poorly defined. Studies in mice demonstrate that AAV2/8 gene transfer to liver is associated with immunological hyporesponsiveness toward both AAV vector and antigenic transgene product. To evaluate the role of activation-induced cell death (AICD) and cytokine withdrawal (intrinsic cell death) in the deletion of mature T lymphocytes, we compared immunological responses in hepatic AAV2/8 transfer in murine recipients lacking the Fas receptor, and recipients overexpressing Bcl-xL, to WT murine counterparts. Prolonged transgene expression was dependent on both Fas signaling and Bcl-xL-regulated apoptosis in T cells. Abrogation of intrinsic cell death enhanced Th1 responses, whereas AICD functioned to limit neutralizing antibody production toward AAV2/8. In addition, immune hyporesponsiveness and stable transgene expression was dependent on upregulation of FasL expression on transduced hepatocytes and a corresponding apoptosis of infiltrating Fas (+) cells. These data provide evidence that both AICD and apoptosis due to cytokine withdrawal of lymphocytes are essential for immune hyporesponsiveness toward hepatic AAV2/8-encoded transgene product in the setting of liver gene transfer.
authors.affiliation: Department of Pathology and Laboratory Medicine, Gene Therapy Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Faust
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhu
authors.forename: Julio
authors.initials: J
authors.lastname: Sanmiguel
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D007108:Immune Tolerance; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D016207:Cytokines; D051020:bcl-X Protein; D019014:fas Receptor