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

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-α), a proinflammatory cytokine, and the related cytokine lymphotoxin α (LTα), in mounting an immune reaction against recombinant adenovirus vectors. After gene transfer in the liver, mice genetically deficient for both cytokines (TNF-α/LTα−/−), 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-α/LTα−/− and TNF-α/LTα+/− mice versus TNF-α/LTα+/+ mice links antibody levels to TNF-α/LTα gene dosage. Due to the absence of neutralizing antibodies, the TNF-α/LTα knockout mice successfully express a second gene transduced by a second vector injection. The discovery of the pivotal role played by TNF-α in controlling the antibody response against adenovirus will allow more efficient adenovirus-based strategies for gene therapy to be proposed.

Innate immunity to adenovirus: lessons from mice

“…Although coagulation FX and natural IgM are the principal blood factors that bind to HAdv in the blood after intravenous virus administration to nonimmune hosts, these factors do not protect the virus from neutralization by HAdv-specific neutralizing antibodies in HAdv-C5 immune hosts. Indeed, liver-directed gene transfer was abrogated upon administering HAdv vector, based on the same serotype that was used for immunization of animals prior to analyzing liver-directed gene delivery [22][23][24]. Intravenous administration of HAdv to hosts with virus-specific immunity leads to the formation of HAdv-antibody (Ab) immune complexes that are sequestered by FcR-positive cells including dendritic cells (DCs), neutrophils [25], and tissue-resident macrophages.…”

Th17 cells and mucosal host defense

“…Although much of clinical HIV-associated risk of infection in the Western world could be understood under this paradigm, this dichotomy of T-cell subsets was incomplete. This particularly became evident as prophylaxis against the opportunistic pathogen Pneumocystis became widespread in the late 80's to the early 90's and bacterial pneumonia increased as a major a pulmonary complication of AIDS [11] [12]. Just like infections ascribed to Th1 or Th2 immunity, epidemiological data also suggested that lung infections with extracellular bacteria were also inversely associated with CD4+ T-cells in peripheral blood [11] [12].…”

Cationic Liposome Conjugation to Recombinant Adenoviral Vector Reduces Viral Antigenicity

“…Presentation of exogenous viral antigens by MHC class II molecules has been suggested to induce the Th1 subset of CD4 + T cells that strengthen the cytotoxic response, as well as the Th2 subset of CD4 + T cells involved in mounting an efficient humoral response by producing tumor necrosis factor alpha (TNF-α) and/or lymphotoxin α (LT α). 18) The B-cell response to an Ad infection consists essentially of IgG antibodies. Since some of these antibodies are neutralizing, efficient redosing is prevented.…”