Adenovirus-mediated gene transfer of viral interleukin-10 inhibits the immune response to both alloantigen and adenoviral antigen.
Although adenoviral vectors are attractive for gene transfer, their effectiveness is limited by host antiviral immune responses. In this study, we determined if host antiallograft and antiviral immunity could be diminished with an adenoviral vector encoding the immunosuppressive cytokine viral interleukin-10 (vIL-10). AdSV40vIL-10, a vIL-10-expressing adenoviral vector with an SV40 promoter, induced significant prolongation of murine cardiac allograft survival to 32.2 +/- 1.7 days compared to 14.2 +/- 1.0 days for controls (p < 0.01). This effect was specific for vIL-10 encoding vector and could be inhibited by anti-vIL-10 monoclonal antibody (mAb). In vivo administration of adenovirus facilitated the generation of adenovirus-specific cytotoxic T lymphocytes (CTL), whereas treatment with AdSV40vIL-10 prevented CTL priming and generation of virus-specific immunity. AdSV40vIL-10 also induced extended expression of a beta-galactosidase reporter from a co-injected LacZ-encoding adenoviral vector. These results demonstrate that adenovirus-mediated gene transfer and expression of vIL-10 prolong allograft survival and inhibit the immune response to adenoviral antigens, thereby improving the persistence of the vector and extending transgene expression. The efficacy of adenoviral vectors can be improved by incorporating immunosuppressive genes into the vector.
Qin
L
L
Department of Surgery, University of Michigan, Ann Arbor 48109-0331, USA.
Ding
Y
Y
Pahud
D R
DR
Robson
N D
ND
Shaked
A
A
Bromberg
J S
JS
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter / Q000235:genetics; D005822:Genetic Vectors; D006085:Graft Survival / Q000276:immunology; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*
D000956:Antigens, Viral; D016207:Cytokines; D007519:Isoantigens; D016753:Interleukin-10