Respective roles of TNF-alpha and IL-6 in the immune response-elicited by adenovirus-mediated gene transfer in mice.
The immunogenicity of recombinant adenoviruses (Ad) constitutes a major concern for their use in gene therapy. Antibody- and cell-mediated immune responses triggered by adenoviral vectors hamper long-term transgene expression and efficient viral readministration. We previously reported that interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha play an essential role in both the acute phase and antibody response against Ad, respectively. As TNF-alpha controls the immune response and the development of the immune system, we examined here the consequence of blockade of TNF-alpha activity through Ad-mediated gene delivery of a dimeric mouse TNFR1-IgG fusion protein on transgene expression from a second Ad. Ad encoding TNFR1-IgG (AdTNFR1-Ig) was injected intravenously along with Ad encoding beta-galactosidase or alpha1-antitrypsin transgene in wild-type (IL-6(+/+)) but also in IL-6-deficient mice (IL-6(-/-)) to analyze how TNF-alpha and IL-6 diminish liver gene transfer efficacy. Blockade of TNF-alpha leads to increased transgene expression in both wild-type and IL-6(-/-) mice due to a reduced inflammatory response and to diminished recruitment of macrophages and NK cells towards the liver. Antibody responses against adenoviral particles and expressed transgenes were only delayed in AdTNFR1-Ig-treated wild-type mice, but were markedly reduced in AdTNFR1-Ig-treated IL-6(-/-) mice. Finally, treatment of mice with etanercept, a clinically approved anti-TNF-alpha drug, confirmed the importance of controlling proinflammatory cytokines during gene therapy by adenoviral vectors.
Benihoud
K
K
Univ Paris-Sud, Faculté des Sciences, Orsay, France. benihoud@igr.fr
Esselin
S
S
Descamps
D
D
Jullienne
B
B
Salone
B
B
Bobé
P
P
Bonardelle
D
D
Connault
E
E
Opolon
P
P
Saggio
I
I
Perricaudet
M
M
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001323:Autoantibodies / Q000097:blood; D004279:DNA, Viral / Q000235:genetics; D000068800:Etanercept; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006505:Hepatitis / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D015850:Interleukin-6 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
D000914:Antibodies, Viral; D001323:Autoantibodies; D004279:DNA, Viral; D007074:Immunoglobulin G; D015850:Interleukin-6; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept