Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors

Yaron Ilan, Renu Prakash, Anne Davidson, Vinod Jona, G. Droguett, Marshall S. Horwitz, Namita Roy Chowdhury, Jayanta Roy Chowdhury

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

Recombinant adenoviruses (Ads) efficiently transfer foreign genes into hepatocytes in vivo, but the duration of transgene expression is limited by the host immune response which precludes gene expression upon readministration of the virus. To test if this immune response can be abrogated by oral tolerization, we instilled protein extracts of a recombinant adenovirus type-5 via gastroduodenostomy tubes into bilirubin- UDP-glucuronosyltransferase-1 (BUGT1)-deficient jaundiced Gunn rats. Control rats received BSA. Subsequent intravenous injection 5 x 109 pfu of a recombinant adenovirus-expressing human BUGT1 (Ad-hBUGT1) resulted in hepatic expression of human BUGT1 (hBUGT1) with reduction of serum bilirubin levels by 70%. After 2 mo serum bilirubin increased gradually. In orally tolerized rats, but not in controls, a second dose of the virus on day 98 markedly reduced serum bilirubin again. In the tolerized rats, the development of antiadenoviral neutralizing antibodies and cytotoxic lymphocytes were markedly inhibited, and transplantation of their splenocytes into naive Gunn rats adoptively transferred the tolerance, indicating a role for regulatory cells. Lymphocytes from the tolerized rats hyperexpressed TGFβ1, IL2, and IL4 upon exposure to viral antigens, whereas IFNγ expression became undetectable. Thus, oral tolerization with adenoviral antigens permits long-term gene expression by repeated injections of recombinant adenoviruses.

Original languageEnglish (US)
Pages (from-to)1098-1106
Number of pages9
JournalJournal of Clinical Investigation
Volume99
Issue number5
DOIs
StatePublished - Mar 1 1997

Keywords

  • Crigler-Najjar syndrome type I
  • Gunn rats
  • UDP- glucuronosyltransferase
  • gene therapy
  • oral tolerization
  • recombinant adenovirus

ASJC Scopus subject areas

  • Medicine(all)

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