Zepeda M, Wilson J M
Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia, USA.
Gene Ther. 1996 Nov;3(11):973-9.
Recombinant adenoviruses are being considered for treatment of cystic fibrosis lung disease. The utility of this vector system in adult recipients is limited by the formation of destructive humoral and cellular immune responses to the vector and vector-infected cells. We hypothesized that the host immune responses could be avoided by administering the vector early in development when the immune system is naive. This was evaluated in the context of newborn and adult cotton rats administered E1-deleted recombinant adenoviral vectors into the trachea. The results with adult cotton rats were consistent with previous studies in that gene expression was extremely high in the conducting airway when evaluated 3 days after administration of the vector. However, expression diminished to undetectable levels within 2 weeks and was associated with substantial inflammation and formation of neutralizing antibodies. The level of expression achieved in newborn cotton rats was equally high with reporter gene expression detected in both the conducting airway and alveolar cells. The immune response in the newborn cotton rats was substantially blunted with diminished CD4+ T cell activation, based on in vitro studies, as well as essentially no formation of neutralizing antibody. This translated to a substantially improved outcome with transgene expression persisting for over 6 months. The window of optimal immune tolerance was within 3 days of birth. Vector was readministered into animals 8-10 weeks after they had received the neonatal challenge of the initial vector. This second delivery of vector was efficient, consistent with the low neutralizing antibody in these animals. However, the animals mounted a full T cell response which correlated with extinction of the transgene from the vector administered at birth, as well as that of the second vector. Neutralizing antibodies did eventually develop following the second vector administration. These studies indicate that immune responses can be avoided if gene therapy is administered early in development. However, this so-called "tolerance' is broken when the animal receives a second vector after the immune system matures.
重组腺病毒正被考虑用于治疗囊性纤维化肺病。这种载体系统在成年受体中的效用受到对载体和载体感染细胞产生的破坏性体液免疫和细胞免疫反应形成的限制。我们假设，当免疫系统处于幼稚状态时，在发育早期给予载体可以避免宿主免疫反应。这在将E1缺失的重组腺病毒载体经气管给予新生和成年棉鼠的背景下进行了评估。成年棉鼠的结果与先前的研究一致，即在给予载体3天后评估时，传导气道中的基因表达极高。然而，表达在2周内降至不可检测水平，并伴有大量炎症和中和抗体的形成。新生棉鼠中实现的表达水平同样很高，在传导气道和肺泡细胞中均检测到报告基因表达。基于体外研究，新生棉鼠中的免疫反应明显减弱，CD4 + T细胞活化减少，并且基本上没有形成中和抗体。这转化为转基因表达持续超过6个月的显著改善结果。最佳免疫耐受窗口在出生后3天内。在动物接受初始载体的新生儿挑战8 - 10周后，将载体重新给予动物。载体的第二次递送是有效的，这与这些动物中低水平的中和抗体一致。然而，动物产生了完全的T细胞反应，这与出生时给予的载体以及第二个载体中的转基因消失相关。在第二次给予载体后，中和抗体最终确实出现了。这些研究表明，如果在发育早期进行基因治疗，可以避免免疫反应。然而，当动物在免疫系统成熟后接受第二个载体时，这种所谓的“耐受性”就会被打破。
