This study explores the genetic and immunologic factors involved in the differences in duration of transgene expression following in vivo transduction with recombinant adenoviruses. Different strains of mice (C3H/HeJ [C3H], C57BL/6J [B6], BALB/cJ [Balb/c], C. B10-H2(b)/LiMcdJ [Balb.B], CB6F1/J [(Balb/c x B6)F1], B6C3F1/J [(B6 x C3H)F1], and BALB/cj SCID) received 5 x 10(9) PFU of the first-generation adenovirus, which expresses human alpha1-antitrypsin (Ad/RSVhAAT). While all strains studied showed similar patterns of anti-adenovirus antibody formation, only Balb/c and C3H mice developed significant levels of anti-hAAT antibodies by 8 weeks posttransduction. In addition, while all strains had quantitatively comparable amounts of adenovirus genomes and hAAT mRNA transcripts in the liver 9 days posttransduction, only Balb/c mice had undetectable adenovirus vector genomes and hAAT mRNA in the liver 40 days posttransduction. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of liver sections from control and Ad/RSVhAAT-infected mice 5, 9, and 40 days posttransduction suggested that apoptosis was involved in the rapid elimination of transduced hepatocytes in Balb/c mice. Persistent expression of hAAT protein observed in BALB/cj SCID mice suggests that antigen-dependent immunity was essential for this apoptotic process in transduced Balb/c hepatocytes. In contrast to Balb/c mice, the loss of expression in C3H mice did not correlate with the loss of vector genomes or hAAT mRNA. Instead, the anti-hAAT antibodies in C3H but not Balb/c mice were found to interfere with detection of hAAT in the serum. In Balb. B and B6 mice, vector genome, hAAT mRNA transcripts, and hAAT protein levels persisted for at least 40 days posttransduction. This persistence correlated with poor anti-hAAT antibody formation and minimal hepatocyte toxicity. The expression of hAAT in (Balb/c x B6)F1 pups was found to be intermediate between the duration observed in the parental strains, while in (C3H x B6)F1 pups hAAT expression was similar to that seen in the B6 parents, which together support polygenic control of the immune responses in these mice. In summary, these findings suggest that there are three different profiles and at least two defined immune system-mediated mechanisms resulting in the loss of hAAT expression in mice and that different strains differ in the capacity to utilize these mechanisms.