Nonspecific Inflammation Inhibits Adenovirus-Mediated Pulmonary Gene Transfer and Expression Independent of Specific Acquired Immune Responses

作者：Kazuhisa Otake, David L. Ennist, Kevin S. Harrod, Bruce C. Trapnell · 发表于：Human Gene Therapy · 年份：1998 · DOI：10.1089/hum.1998.9.15-2207 · 被引用次数：142 · 研究领域：Virus-based gene therapy research、Respiratory viral infections research、Viral gastroenteritis research and epidemiology

Replication-deficient adenovirus vectors (Avs) have shown high-efficiency gene transfer in a variety of animal models, but demonstrated lower than expected efficiency in the intensely inflammatory milieu of the respiratory tract of individuals with cystic fibrosis (CF). Specific acquired immune responses directed at adenovirus capsid proteins are known to limit the duration of transgene expression and the effectiveness of vector readministration. In these models, however, nonspecific inflammation is also frequently noted to accompany specific immune responses. Because inflammation can occur early after Av administration, we hypothesized that inflammation may block Av-mediated gene transfer in the lung independent of specific immune responses. To evaluate this hypothesis, we measured pulmonary gene transfer and expression in the absence or presence of the potent antiinflammatory agent dexamethasone. To address and eliminate concerns over the potentially confounding effects of systemic, vector-specific acquired immune responses, evaluations were confined to a 3-day period following Av administration and were carried out, in parallel, in normal and immunodeficient (athymic) mice. Dexamethasone significantly reduced Av-associated inflammation in all animals as measured by a significant reduction of blinded, quantitative lung histopathology scores and by reduced proinflammatory cytokine release. Concomitant with reduced inflammation, gene transfer efficiency was significantly incr...