Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat

Yaron Ilan, Vinod K. Jona, Krishna Sengupta, Anne Davidson, Marshall S. Horwitz, Namita Roy-Chowdhury, Jayanta Roy-Chowdhury

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)949-956
Number of pages8
JournalHepatology
Volume26
Issue number4
StatePublished - Oct 1997

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Tacrolimus
Adenoviridae
Immunosuppression
Viruses
Gene Expression
Liver
Injections
Bilirubin
Cytotoxic T-Lymphocytes
Therapeutics
Gunn Rats
Galactosidases
Human Adenoviruses
Control Groups
Immunosuppressive Agents
Neutralizing Antibodies
Serum
Genetic Therapy
Escherichia coli
Antibodies

ASJC Scopus subject areas

  • Hepatology

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Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat. / Ilan, Yaron; Jona, Vinod K.; Sengupta, Krishna; Davidson, Anne; Horwitz, Marshall S.; Roy-Chowdhury, Namita; Roy-Chowdhury, Jayanta.

In: Hepatology, Vol. 26, No. 4, 10.1997, p. 949-956.

Research output: Contribution to journalArticle

Ilan, Yaron ; Jona, Vinod K. ; Sengupta, Krishna ; Davidson, Anne ; Horwitz, Marshall S. ; Roy-Chowdhury, Namita ; Roy-Chowdhury, Jayanta. / Transient immunosuppression with FK506 permits long-term expression of therapeutic genes introduced into the liver using recombinant adenoviruses in the rat. In: Hepatology. 1997 ; Vol. 26, No. 4. pp. 949-956.
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