Effects of bronchopulmonary inflammation induced by Pseudomonas aeruginosa on adenovirus-mediated gene transfer to airway epithelial cells in mice

Effect of Pseudomonas-induced chronic lung inflammation on specific cytotoxic T-cell responses to adenoviral vectors in mice

“…Each of these three cytokines is also present at very high concentrations in BAL of patients with CF and chronic Pseudomonas lung infection. 18 In addition, as in our previously published studies, 17 histopathologic examination of the lungs of representative groups of mice 7 days after inoculation with Pseudomonas-laden or sterile beads confirmed a fivefold or greater increase in areal lung inflammation for mice that received the Pseudomonas-laden beads compared to sterile bead controls (not shown), with inflammatory cell infiltrates similar to those observed in lung sections from patients with CF. Thus, the inflammatory features of the mouse model employed in the current studies are similar to those of CF lung disease.…”

“…Previous data from our laboratory, 17 taken together with the current studies, suggest that the Pseudomonas-induced chronic inflammatory airway milieu in CF may provide both its own direct physical or biochemical impediments to Ad-mediated gene transfer and may additionally intensify some of the immunologic responses that, even in the absence of pre-existing lung inflammation, have been associated with reduced duration of Ad-mediated transgene expression. Our findings emphasize the importance of considering the influence of the existing state of inflammation in the CF airway, when testing gene delivery systems in animal models with a view toward treatment of patients with this disease.…”

“…Our current findings indicate that Ad-specific CTL responses are markedly enhanced in this setting, although antibody responses appear not to be changed significantly. Thus, the environment of chronic Pseudomonas infection in the airways not only reduces shortterm transgene expression, as we have published previously, 17 but also may interfere indirectly with the duration of transgene expression by increasing the extent to which transduced epithelial cells are destroyed by specific CTL responses.…”

“…15,16 In previous studies, we reported that chronic Pseudomonas-induced lung inflammation in mice reduced the extent of Ad-mediated gene transfer in the airways. 17 As the milieu of the chronically infected lung in CF patients contains a number of cytokines and other mediators that may influence inflammatory and immune responses, 18 we proposed that specific immune responses already known to interfere with Ad-mediated transgene delivery and expression, even in the absence of pre-existing inflammation, may be exaggerated in a setting of chronic Pseudomonas-induced airway inflammation in mice, similar to that found in the airways of CF patients.…”

“…It is worth noting that our previously published data demonstrated a marked reduction (X60%) in short-term Ad-mediated transgene expression for mice infected in the chronic Pseudomonas agarose bead model. 17 As this implies a concomitant reduction in synthesis of viral and transgene antigens available to stimulate the afferent limb of the immune response, it is possible that, in the chronically inflamed lung, these afferent mechanisms may be stimulated to an even greater relative degree than the currently observed enhancement of the relevant effector response (CTL activity) would suggest. It is also important to recognize that relatively long-term expression of a nonimmunogenic transgene has been observed in several models despite the presence of Ad-specific CTLs, suggesting that, in some cases, CTLs specific for the transgene product may be at least as important as those directed against the vector itself.…”