Oral tolerization to adenoviral proteins permits repeated adenovirus- mediated gene therapy in rats with pre-existing immunity to adenoviruses

Yaron Ilan, Bernhard Sauter, Namita Roy Chowdhury, Bhoompally V N Reddy, Narsing R. Thummala, Gustavo Droguett, Anne Davidson, Michael Olt, Marshall S. Horwitz, Jayanta Roy-Chowdhury

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Abstract

Exposure to wild-type adenoviruses is common in humans and results in immune response against adenoviruses. The pre-existing antibodies and a strong secondary humoral and cellular immune response would interfere with gene transfer using recombinant adenoviral vectors. To test whether the secondary immune response can be abrogated by oral tolerization to adenoviral antigens, we immunized bilirubin-UDP-glucuronosyltransferase (BUGT)-deficient jaundiced Gunn rats with a recombinant adenovirus (5 x 109 pfu/rat) expressing the human UDP-glucouronosyltransferase (BUGT1) gene (Ad-hBUGT). Transgene expression was shown by reduction of mean serum bilirubin levels from 7.0 mg/dL to 2.3 mg/dL in 14 days, which then increased gradually to pretreatment levels in 6 weeks. All recipients developed antibodies (1:210) and cytotoxic lymphocytes against the adenovirus. For oral tolerization, we administered to the immunized rats protein extracts of a recombinant adenovirus type 5 (1-1.5 mg/day) via duodenostomy tubes 10 to 40 days after the initial virus injection; control rats received bovine serum albumin. In rats fed adenoviral proteins and the BSA-fed controls, the antibody titers decreased to 1:27 and 1:29, respectively, in 70 days. Lymphocytes from the tolerized rats expressed TGF-β1 upon exposure to antigen-presenting cells primed with adenoviral antigens, whereas IFN-γ expression was undetectable. In contrast, lymphocytes from the BSA-treated control rats expressed IFN-γ but not transforming growth factor β1 (TGF-β1). Seventy days after the first injection in the orally tolerized rats, but not in the controls, a second Ad-hBUGT injection caused human BUGT1 expression again, reducing serum bilirubin levels to those observed after the first injection. In the tolerized rats, serum antibody titers and anti-adenoviral cytotoxic lymphocyte activities continued to decline despite the second injection, whereas the antibody levels were boosted in the non-tolerized group. This results show that by preventing the secondary booster response, oral tolerization permits repeated adenovirus-directed gene transfer despite the presence of a residual antibody titer from a previous adenoviral exposure.

Original languageEnglish (US)
Pages (from-to)1368-1376
Number of pages9
JournalHepatology
Volume27
Issue number5
DOIs
StatePublished - 1998

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Adenoviridae
Genetic Therapy
Immunity
Proteins
Injections
Antibodies
Lymphocytes
bilirubin glucuronoside glucuronosyltransferase
Transforming Growth Factors
Bilirubin
Duodenostomy
Gunn Rats
Serum
Genes
Antigens
Uridine Diphosphate
Antigen-Presenting Cells
Humoral Immunity
Bovine Serum Albumin
Jaundice

ASJC Scopus subject areas

  • Hepatology

Cite this

Oral tolerization to adenoviral proteins permits repeated adenovirus- mediated gene therapy in rats with pre-existing immunity to adenoviruses. / Ilan, Yaron; Sauter, Bernhard; Chowdhury, Namita Roy; Reddy, Bhoompally V N; Thummala, Narsing R.; Droguett, Gustavo; Davidson, Anne; Olt, Michael; Horwitz, Marshall S.; Roy-Chowdhury, Jayanta.

In: Hepatology, Vol. 27, No. 5, 1998, p. 1368-1376.

Research output: Contribution to journalArticle

Ilan, Y, Sauter, B, Chowdhury, NR, Reddy, BVN, Thummala, NR, Droguett, G, Davidson, A, Olt, M, Horwitz, MS & Roy-Chowdhury, J 1998, 'Oral tolerization to adenoviral proteins permits repeated adenovirus- mediated gene therapy in rats with pre-existing immunity to adenoviruses', Hepatology, vol. 27, no. 5, pp. 1368-1376. https://doi.org/10.1002/hep.510270525
Ilan, Yaron ; Sauter, Bernhard ; Chowdhury, Namita Roy ; Reddy, Bhoompally V N ; Thummala, Narsing R. ; Droguett, Gustavo ; Davidson, Anne ; Olt, Michael ; Horwitz, Marshall S. ; Roy-Chowdhury, Jayanta. / Oral tolerization to adenoviral proteins permits repeated adenovirus- mediated gene therapy in rats with pre-existing immunity to adenoviruses. In: Hepatology. 1998 ; Vol. 27, No. 5. pp. 1368-1376.
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AU - Reddy, Bhoompally V N

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