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PMID: 9811684 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Efficient, repeated adenovirus-mediated gene transfer in mice lacking both tumor necrosis factor alpha and lymphotoxin alpha.

Journal of virology ·Vol. 72 ·No. 12 ·1998-12-00 ·Pages 9514-25

Benihoud K, Saggio I, Opolon P, Salone B, Amiot F, Connault E, Chianale C, Dautry F, Yeh P, Perricaudet M

Abstract

The efficiency of adenovirus-mediated gene transfer is now well established. However, the cellular and the humoral immune responses triggered by vector injection lead to the rapid elimination of the transduced cells and preclude any efficient readministration. The present investigation focuses on the role of tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, and the related cytokine lymphotoxin alpha (LTalpha), in mounting an immune reaction against recombinant adenovirus vectors. After gene transfer in the liver, mice genetically deficient for both cytokines (TNF-alpha/LTalpha-/-), in comparison with normal mice, presented a weak acute-phase inflammatory reaction, a reduction in cellular infiltrates in the liver, and a severely impaired T-cell proliferative response to both Adenoviral and transgene product antigens. Moreover, we observed a strong reduction in the humoral response to the vector and the transgene product, with a drastic reduction of anti-adenovirus immunoglobulin A and G antibody isotypes. In addition, the reduction in antibody response observed in TNF-alpha/LTalpha-/- and TNF-alpha/LTalpha+/- mice versus TNF-alpha/LTalpha+/+ mice links antibody levels to TNF-alpha/LTalpha gene dosage. Due to the absence of neutralizing antibodies, the TNF-alpha/LTalpha knockout mice successfully express a second gene transduced by a second vector injection. The discovery of the pivotal role played by TNF-alpha in controlling the antibody response against adenovirus will allow more efficient adenovirus-based strategies for gene therapy to be proposed.

MeSH Terms
Acute-Phase Reaction Animals Antibodies, Viral/biosynthesis Gene Expression Gene Transfer Techniques Genetic Therapy Genetic Vectors Immunity, Cellular In Vitro Techniques Liver/immunology,virology Lymphocyte Activation Lymphotoxin-alpha/genetics,physiology Mastadenovirus/genetics,immunology,pathogenicity Mice Mice, Inbred C57BL Mice, Knockout Neutralization Tests Recombination, Genetic Tumor Necrosis Factor-alpha/deficiency,genetics,physiology
Chemicals
Antibodies, Viral Lymphotoxin-alpha Tumor Necrosis Factor-alpha
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Benihoud K
CNRS UMR1582/Rhône Poulenc Gencell/IGR, Institut Gustave Roussy, 94805 Villejuif Cedex, France. benihoud@igr.fr
Saggio I
Opolon P
Salone B
Amiot F
Connault E
Chianale C
Dautry F
Yeh P
Perricaudet M
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.72.12.9514-9525.1998
Email
benihoud@igr.fr
Published
1998-12-00
Pages
9514-25
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC110450
Subset
IM
External Links
PubMed source DOI: 10.1128/JVI.72.12.9514-9525.1998 PMC Full Text View journal details
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