Title: Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat
Abstract: HepatologyVolume 26, Issue 4 p. 949-956 Original ArticleFree Access Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat Y Ilan, Y Ilan Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorV K Jona, V K Jona Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorK Sengupta, K Sengupta Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorA Davidson, A Davidson Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorM S Horwitz, M S Horwitz Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorN Roy-Chowdhury, N Roy-Chowdhury Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorJ Roy-Chowdhury, J Roy-Chowdhury Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this author Y Ilan, Y Ilan Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorV K Jona, V K Jona Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorK Sengupta, K Sengupta Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorA Davidson, A Davidson Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorM S Horwitz, M S Horwitz Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorN Roy-Chowdhury, N Roy-Chowdhury Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this authorJ Roy-Chowdhury, J Roy-Chowdhury Marion Bessin Liver Research Center, Division of Gastroenterology, Albert Einstein College of Medicine, Bronx, New York 10461, USASearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1002/hep.510260422Citations: 85AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract The host immune response limits the duration of expression of adenovirally transduced genes and precludes long-term gene expression upon re-administration of the virus. In this study we wished to evaluate whether short-term immunosuppression of the host, at the time of recombinant virus administration, would allow expression of the therapeutic gene product upon virus reinjection. Gunn rats were used as recipients of recombinant adenoviruses expressing human BUGT (Ad-hBUGT) or E. coli β-galactosidase (Ad-LacZ). Rats were treated with FK506 (1-1.5 mg/kg, per OS daily) for three days beginning 24 hours before each virus injection. Control groups did not receive any immunosuppressant. The serum bilirubin level was reduced from 7.1 ± 0.75 mg/dL to 2.0 ± 0.7 mg/dL within two days of viral injection in both FK506 treated and control groups, and then gradually increased in 6 weeks. FK506-treated rats had low or undetectable antibody titers against the recombinant adenovirus and minimal or no cytotoxic T lymphocyte (CTL) response against adenovirus-infected cells. The tolerized rats received two subsequent injections 42 and 98 days after the first injection, which reduced the bilirubin levels again to 2.0 ± 0.56 and 2.2 ± 0.61 mg/dL, respectively. In contrast, control rats developed high titer neutralizing antibodies and a CTL response, and their serum bilirubin levels were not reduced following subsequent injections. We conclude that short-term FK506 treatment around the time of virus administration prevents the host immune response, permitting long-term gene therapy by repeated administration of the recombinant virus. References 1 Wilson JM, Jefferson DM, Chowdury J Roy, Novikoff PM, Johnston DM, Mulligan RC. Retrovirus mediated transduction of adult hepatocytes. Proc Natl Acad Sci U S A 1988; 85: 3014– 3018. 2 Ali M, Lemoine NR, Ring CJA. 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