Adenovirus-mediated gene transfer: Influence of transgene, mouse strain and type of immune response on persistence of transgene expression

E1-deleted adenovirus (Ad) vectors expressing the human coagulation factor IX (hFIX) or the bacterial beta-galactosidase (lacZ) were injected intravenously into various strains of immunocompetent (C57Bl/6, BALB/c, CD1, CBA/J, C3H) and immunodeficient (BALB/c-nu/nu, C57Bl/6-nu/nu, SCID, NIH-bg-nu-xid) mice. Regular analysis of mouse sera and tissues showed a persistent expression of both transgenes in immunodeficient mice, while detection diminished very rapidly in immunocompetent mice. The mechanisms responsible for the transient detection of the two transgenes were however not identical. Rapid decline of lacZ expression was correlated with a rapid decrease of viral DNA sequences, and consequently to the induction of a cellular immune response to the lacZ antigen. In contrast, absence of detectable levels of serum hFIX in immunocompetent animals was not associated with a loss of viral DNA but was strictly correlated with the induction of anti-hFIX antibodies. Surprisingly, anti-hFIX antibodies were never detected in C57Bl/6 mice, leading to prolonged defection of hFIX. These results suggest that cellular immunity to viral antigens plays a minor role in the early extinction of transgene expression and illustrate the influence of the cellular (eg lacZ) or humoral (eg hFIX) immunity to transgene-encoded products on the persistence of transgene expression.