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
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.