title: Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo.
abstract: Replication-deficient adenoviruses are known to induce acute injury and inflammation of infected tissues, thus limiting their use for human gene therapy. However, molecular mechanisms triggering this response have not been fully defined. To characterize this response, chemokine expression was evaluated in DBA/2 mice following the intravenous administration of various adenoviral vectors. Administration of adCMVbeta gal, adCMV-GFP, or FG140 intravenously rapidly induced a consistent pattern of C-X-C and C-C chemokine expression in mouse liver in a dose-dependent fashion. One hour following infection with 10(10) PFU of adCMVbeta gal, hepatic levels of MIP-2 mRNA were increased >60-fold over baseline. MCP-1 and IP-10 mRNA levels were also increased immediately following infection with various adenoviral vectors, peaking at 6 hr with >25- and >100-fold expression, respectively. Early induction of RANTES and MIP-1beta mRNA by adenoviral vectors also occurred, but to a lesser degree. The induction of chemokines occurred independently of viral gene expression since psoralen-inactivated adenoviral particles produced an identical pattern of chemokine gene transcription within the first 16 hr of administration. The expression of chemokines correlated as expected with the influx of neutrophils and CD11b+ cells into the livers of infected animals. At high titers, all adenoviral vectors caused significant hepatic necrosis and apoptosis following systemic administration to DBA/2 mice. To investigate the role of neutrophils in this adenovirus-induced hepatic injury, animals were pretreated with neutralizing anti-MIP-2 antibodies or depleted of neutrophils. MIP-2 antagonism and neutrophil depletion both resulted in reduced serum ALT/AST levels and attenuation of the adenovirus-induced hepatic injury histologically, confirming that this early injury is largely due to chemokine production and neutrophil recruitment. Our findings further clarify the early immune response against replication-deficient adenoviral vectors and suggest a strategy to prevent adenovirus-mediated inflammation and tissue injury by interfering with chemokine or neutrophil function.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Muruve
authors.forename: M J
authors.initials: MJ
authors.lastname: Barnes
authors.forename: I E
authors.initials: IE
authors.lastname: Stillman
authors.forename: T A
authors.initials: TA
authors.lastname: Libermann
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002213:Capsid / Q000502:physiology; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis*; D017931:DNA Primers; D015316:Genetic Therapy; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008212:Lymphocyte Depletion; D051379:Mice; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000502:physiology*
chemical_list: D018925:Chemokines; D017931:DNA Primers