TY - JOUR
T1 - Oral tolerization to adenoviral antigens permits long-term gene expression using recombinant adenoviral vectors
AU - Ilan, Yaron
AU - Prakash, Renu
AU - Davidson, Anne
AU - Jona, Vinod
AU - Droguett, G.
AU - Horwitz, Marshall S.
AU - Chowdhury, Namita Roy
AU - Chowdhury, Jayanta Roy
PY - 1997/3/1
Y1 - 1997/3/1
N2 - 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.
AB - 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.
KW - Crigler-Najjar syndrome type I
KW - Gunn rats
KW - UDP- glucuronosyltransferase
KW - gene therapy
KW - oral tolerization
KW - recombinant adenovirus
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U2 - 10.1172/JCI119238
DO - 10.1172/JCI119238
M3 - Article
C2 - 9062369
AN - SCOPUS:0030951645
SN - 0021-9738
VL - 99
SP - 1098
EP - 1106
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -