Effect of immune response on gene transfer to the lung via systemic administration of cationic lipidic vectors

Cationic lipid-mediated intravenous gene delivery shows promise in treating pulmonary diseases including lung tumor metastases, pulmonary hypertension , and acute respiratory distress syndrome. Nevertheless, clinical applicati ons of cationic lipidic vectors via intravenous administration are limited by their transient gene expression. In addition, repeated dosing is not eff ective at frequent intervals. In an effort to elucidate the mechanism of ge ne inactivation, we report in this study that cationic lipid-protamine-DNA (LPD) complexes, but not each component alone, can induce a high level of c ytokine production, including interferon-gamma and tumor necrosis factor-al pha. Furthermore, we demonstrate that LPD administration triggers apoptosis in the lung, a phenomenon that may be mediated in part by the two cytokine s. Treatment of mice with antibodies against the two cytokines prolongs the duration of gene expression and also improves lung transfection on a secon d administration of LPD. Although the mechanism underlying LPD-induced cyto kine production is unclear, methylation of the DNA significantly decreased the level of both interferon-gamma and tumor necrosis factor-alpha, suggest ing that unmethylated CpG sequences in plasmid DNA play an important role. These data suggest that decreasing the CpG-mediated immune response while n ot affecting gene expression may be a useful therapeutic strategy to improv e cationic lipid-mediated intravenous gene delivery to the lung.