Insertion of the adenoviral E3 region into a recombinant viral vector prevents antiviral humoral and cellular immune responses and permits long-term gene expression

被引:165
作者
Ilan, Y
Droguett, G
Chowdhury, NR
Li, YA
Sengupta, K
Thummala, NR
Davidson, A
Chowdhury, JR
Horwitz, MS
机构
[1] ALBERT EINSTEIN COLL MED, DEPT MICROBIOL & IMMUNOL, BRONX, NY 10461 USA
[2] ALBERT EINSTEIN COLL MED, DEPT MED, BRONX, NY 10461 USA
[3] ALBERT EINSTEIN COLL MED, DEPT MOL GENET, BRONX, NY 10461 USA
[4] ALBERT EINSTEIN COLL MED, DEPT PEDIAT, BRONX, NY 10461 USA
[5] ALBERT EINSTEIN COLL MED, MARION BESSIN LIVER RES CTR, BRONX, NY 10461 USA
关键词
CYSTIC-FIBROSIS; RAT-LIVER; THERAPY; GLUCURONOSYLTRANSFERASE; HEPATOCYTES; ANTIGENS; PROTEINS; ANTIBODY; SYSTEM; TISSUE;
D O I
10.1073/pnas.94.6.2587
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Recombinant adenoviruses (Ads) are highly efficient at transferring foreign genes to the liver in vivo; however, the duration of gene expression is limited by the host antiviral immune response, which prevents expression upon readministration of the virus, To test whether overexpression of the immunomodulatory products of the early Ad genome region 3 (E3) could prevent the antiviral immune response and prolong expression of foreign genes delivered by Ad vectors, we injected a recombinant Ad (Ad-E3-hBUGT), containing both E3 and the human bilirubin-uridine-diphosphoglucuronate-glucuronosyltransferase (BUGT) genes, into BUGT-deficient hyperbilirubinemic Gunn rats, Control Gunn rats received Ad-hBUGT, which expresses human BUGT alone, An initial injection of either virus resulted in hepatic expression of human BUGT as evidenced by excretion of bilirubin glucuronides in bile and a reduction of mean serum bilirubin levels from 7.0 mg/dl to 1.9-2.7 mg/dl within 7 days, In Ad-E3-hBUGT-injected rats, serum bilirubin levels increased to 4.5 mg/dl by 84 days after infection, but a second administration of the virus on that day resulted in a hypobilirubinemic response similar to that seen with the first injection, In contrast, rats receiving Ad-hBUGT had serum bilirubin levels of 7 mg/dl on day 84 after infection, but showed no reduction of serum bilirubin by reinjection of the virus on that day, In the rats injected with Ad-E3-hBUGT, but not in the ones injected with Ad-hBUGT, there was a marked inhibition of the antiviral antibody and Ad specific cytotoxic T lymphocyte responses, This is the first demonstration that insertion of E3 genes in recombinant Ads facilitates readministration of a functional vector for long-term correction of an inherited metabolic disorder.
引用
收藏
页码:2587 / 2592
页数:6
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