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

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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 immuneresponses triggered by vector injection lead to the rapid eliminationof the transduced cells and preclude any efficient readministration.The present investigation focuses on the role of tumor necrosisfactor alpha (TNF- $alpha$ ), a proinflammatory cytokine, and the relatedcytokine lymphotoxin $alpha$ (LT $alpha$ ), in mounting an immune reaction againstrecombinant adenovirus vectors. After gene transfer in the liver,mice genetically deficient for both cytokines (TNF- $alpha$ /LT $alpha$ ^/), in comparison with normal mice, presented a weak acute-phaseinflammatory reaction, a reduction in cellular infiltrates inthe liver, and a severely impaired T-cell proliferative responseto both Adenoviral and transgene product antigens. Moreover, weobserved a strong reduction in the humoral response to the vectorand the transgene product, with a drastic reduction of anti-adenovirusimmunoglobulin A and G antibody isotypes. In addition, the reductionin antibody response observed in TNF- $alpha$ /LT $alpha$ ^/ and TNF- $alpha$ /LT $alpha$ ^+/ mice versus TNF- $alpha$ /LT $alpha$ ^+/+ mice links antibody levels to TNF- $alpha$ /LT $alpha$ gene dosage. Due to theabsence of neutralizing antibodies, the TNF- $alpha$ /LT $alpha$ knockout micesuccessfully express a second gene transduced by a second vectorinjection. The discovery of the pivotal role played by TNF- $alpha$ incontrolling the antibody response against adenovirus will allowmore efficient adenovirus-based strategies for gene therapy tobeproposed.

^* 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, 94805Villejuif 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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