One barrier to the successful application of gene therapy is that although many options exist for transfecting cells in vitro, these techniques are often not easily adapted for in vivo use. This is particularly true for attempts to reverse immunodeficiency in the lung. Alveolar macophages (AMs) are essential for the generation of an effective inflammatory response against pathogens invading the alveolar space. During systemic immunosuppression, the function of these phagocytic cells diminishes, and the risk of opportunistic lung infections increases. Wu and colleagues now describe, in Proceedings of the National Academy of Sciences, an approach to reverse alveolar immunodeficiency through transferring the mouse interferon-γ (Ifnγ) gene into AMs ex vivo, before airway delivery of the genetically modified cells.

The authors used a recombinant retroviral system to produce IFN-γ-expressing retrovirus with which they infected a mouse macrophage cell line, J774A.1. Transduced cells produced significant levels of IFN-γ, whereas none was detected in the culture supernatent of uninfected cells. Next, the IFN-γ-producing macrophages were transferred intratracheally into severe combined immunodeficient (scid) mice. IFN-γ was readily detected in the bronchoalveolar lavage (BAL) fluid from these mice, in contrast to mice instilled with macrophages infected with control virus. Although the expression levels of IFN-γ gradually decreased, it was still detectable in BAL fluid 1 month after instillation.

How did the overexpression of IFN-γ in the alveolar spaces of the recipient mice affect immune function? AM function was partially restored, resulting in enhanced MHC class II expression and increased phagocytic activity of these cells, detectable even 14 days after instillation of IFN-γ-producing macrophages. In addition, increased levels of the pro-inflammatory cytokine tumour necrosis factor-α were present in the BAL fluid of recipient mice.

The authors conclude that the airway delivery of genetically engineered macrophages expressing IFN-γ can enhance immune activity in the alveolar spaces of immunodeficient animals, and that this approach might be appplicable for gene therapy of immunocompromised patients who are susceptible to opportunistic lung infections.