Persistent and secondary adenovirus-mediated hepatic gene expression using adenovirus vector containing CTLA4IgG.
Adenovirus vectors can transfer recombinant genes efficiently into a wide variety of cells in vivo, but have serious limitations: gene expression is transient and secondary gene transfer is inefficient or impossible because of cellular and humoral immune responses against adenovirus-transduced cells. To solve these limitations, we have constructed an adenovirus vector, Adex1CACTLA4IgG, that expresses CTLA4IgG molecules. After in vivo administration of Adex1CACTLA4IgG (9.0 x 10(9) PFU), the peak level of serum CTLA4IgG was 29.8 mg/ml on day 4. The serum CTLA4IgG concentration gradually fell but was still 5.7 mg/ml on day 90. However, the serum concentration of CTLA4IgG was elevated after a second administration of Adex1CACTLA4IgG. The production of antibody against adenovirus was completely prevented after treatment with Adex1CACTLA4IgG. In addition, coadministration of Adex1CALacZ with Adex1CACTLA4IgG induced persistent hepatic expression of beta-Gal molecules, while administration of Adex1CALacZ alone induced transient expression of beta-Gal molecules. More importantly, on day 160 a secondary challenge with Adex1CALacZ was possible in mice treated with Adex1CALacZ plus Adex1CACTLA4IgG. Thus, we have demonstrated that (1) gene expression of a recombinant adenovirus, Adex1CACTLA4IgG, is persistent in liver and secondary administration of this adenovirus is possible, (2) coadministration of Adex1CACTLA4IgG virus with another adenovirus, AdexCALacZ, prolongs AdexCALacZ-mediated gene expression, and (3) Adex1CACTLA4IgG is useful for secondary challenge with Adex1CALacZ.
Institute of Immunological Science, Department of Cardiovascular Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
I
I
Nakagawa
M
M
Murakami
K
K
Ijima
S
S
Chikuma
I
I
Saito
Y
Y
Kanegae
H
H
Ishikura
T
T
Yoshiki
H
H
Okamoto
A
A
Kitabatake
T
T
Uede
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000097:blood / Q000235:genetics*; D060908:CTLA-4 Antigen; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000097:blood / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008808:Mice, Inbred CBA
D000914:Antibodies, Viral; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D000069594:Abatacept