ORAL TOLERIZATION TO ADENOVIRAL ANTIGENS PERMITS LONG-TERM GENE-EXPRESSION USING RECOMBINANT ADENOVIRAL VECTORS

Citation
Y. Ilan et al., ORAL TOLERIZATION TO ADENOVIRAL ANTIGENS PERMITS LONG-TERM GENE-EXPRESSION USING RECOMBINANT ADENOVIRAL VECTORS, The Journal of clinical investigation, 99(5), 1997, pp. 1098-1106
Citations number
52
Categorie Soggetti
Medicine, Research & Experimental
ISSN journal
00219738
Volume
99
Issue
5
Year of publication
1997
Pages
1098 - 1106
Database
ISI
SICI code
0021-9738(1997)99:5<1098:OTTAAP>2.0.ZU;2-G
Abstract
Recombinant adenoviruses (Ads) efficiently transfer foreign genes into hepatocytes in vivo, but the duration of transgene expression is limi ted by the host immune response which precludes gene expression upon r eadministration of the virus, To test if this immune response can be a brogated by oral tolerization, we instilled protein extracts of a reco mbinant adenovirus type-5 via gastroduodenostomy tubes into bilirubin- UDP-glucuronosyltransferase-1 (BUGT(1))-deficient jaundiced Gunn rats, Control rats received BSA, Subsequent intravenous injection 5 x 10(9) pfu of a recombinant adenovirus-expressing human BUGT(1) (Ad-hBUGT(1) ) resulted in hepatic expression of human BUGT(1) (hBUGT(1)) with redu ction of serum bilirubin levels by 70%. After 2 mo serum bilirubin inc reased gradually, In orally tolerized rats, but not in controls, a sec ond dose of the virus on day 98 markedly reduced serum bilirubin again . In the tolerized rats, the development of antiadenoviral neutralizin g antibodies and cytotoxic lymphocytes were markedly inhibited, and tr ansplantation of their splenocytes into naive Gunn rats adoptively tra nsferred the tolerance, indicating a role for regulatory cells. Lympho cytes from the tolerized rats hyperexpressed TGF beta(1), IL2, and IL4 upon exposure to viral antigens, whereas IFN gamma expression became undetectable, Thus, oral tolerization with adenoviral antigens permits long-term gene expression by repeated injections of recombinant adeno viruses.