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Journal of Virology, December 1998, p. 9514-9525, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Efficient, Repeated Adenovirus-Mediated Gene Transfer in Mice Lacking both Tumor Necrosis Factor Alpha and Lymphotoxin alpha

Karim Benihoud,1,* Isabella Saggio,2 Paule Opolon,1 Barbara Salone,2 Franck Amiot,3 Elisabeth Connault,1 Colette Chianale,4 François Dautry,3 Patrice Yeh,1 and Michel Perricaudet1

CNRS UMR1582/Rhône Poulenc Gencell/IGR1 and Service d'Expérimentation Animale,4 Institut Gustave Roussy, 94805 Villejuif Cedex, and CNRS UPR9044, Institut de Recherche sur le Cancer, 94807 Villejuif Cedex,3 France, and Dipartimento di Genetica, Universita di Roma "La Sapienza," 00185 Rome, Italy2

Received 23 February 1998/Accepted 20 August 1998

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.

* Corresponding author. Mailing address: Laboratoire de Vectorologie et Transfert de Gènes, UMR1582 CNRS/Rhône Poulenc Gencell/IGR, Institut Gustave Roussy PR2, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France. Phone: (33) 1 42 11 50 82. Fax: (33) 1 42 11 52 45. E-mail: benihoud{at}igr.fr.

Journal of Virology, December 1998, p. 9514-9525, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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