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 fa ctor IX (hFIX) or the bacterial beta-galactosidase (lacZ) were injecte d 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 tra nsgenes were however not identical. Rapid decline of lacZ expression w as correlated with a rapid decrease of viral DNA sequences, and conseq uently to the induction of a cellular immune response to the lacZ anti gen. In contrast, absence of detectable levels of serum hFIX in immuno competent animals was not associated with a loss of viral DNA but was strictly correlated with the induction of anti-hFIX antibodies. Surpri singly, anti-hFIX antibodies were never detected in C57Bl/6 mice, lead ing to prolonged defection of hFIX. These results suggest that cellula r immunity to viral antigens plays a minor role in the early extinctio n 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.