EFFICIENT, REPEATED ADENOVIRUS-MEDIATED GENE-TRANSFER IN MICE LACKINGBOTH TUMOR-NECROSIS-FACTOR-ALPHA AND LYMPHOTOXIN-ALPHA

The efficiency of adenovirus-mediated gene transfer is now well establ ished. However, the cellular and the humoral immune responses triggere d by vector injection lead to the rapid elimination of the transduced cells and preclude any efficient readministration. The present investi gation focuses on the role of tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, and the related cytokine lymphotoxin alph a (LT alpha), in mounting an immune reaction against recombinant adeno virus vectors. After gene transfer in the liver, mice genetically defi cient for both cytokines (TNF-alpha/LT alpha(-/-)), in comparison with normal mice, presented a weak acute-phase inflammatory reaction, a re duction 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 res ponse to the vector and the transgene product, with a drastic reductio n of anti-adenovirus immunoglobulin A and G antibody isotypes. In addi tion, the reduction in antibody response observed in TNF-alpha/LT alph a(-/-) and TNF-alpha/LT alpha(+/-) mice versus TNF-alpha/LTa+/+ mice l inks antibody levels to TNF-alpha/LT alpha gene dosage. Due to the abs ence of neutralizing antibodies, the TNF-alpha/LT alpha knockout mice successfully express a second gene transduced by a second vector injec tion. The discovery of the pivotal role played by TNF-alpha in control ling the antibody response against adenovirus will allow more efficien t adenovirus-based strategies for gene therapy to be proposed.