Lei D, Lehmann M, Shellito J E, Nelson S, Siegling A, Volk H D, Kolls J K
LSU Section of Pulmonary/Critical Care MEB, New Orleans 70112, USA.
Hum Gene Ther. 1996 Dec 1;7(18):2273-9. doi: 10.1089/hum.1996.7.18-2273.
E1-deleted adenoviral vectors are efficient vectors for somatic cell gene therapy, but transgene expression is limited in part by a cytotoxic T cell response directed against virally transduced cells. Moreover, the development of a neutralizing antibody response limits secondary gene transfer with these vectors. Therapy with a depleting anti-CD4 antibody permits prolonged transgene expression in the lung and liver of mice. Furthermore, transient depletion of CD4+ lymphocytes blocks neutralizing antibody production and therefore allows repeat administration and expression of E1-deleted recombinant adenovirus. In this study, we investigated the efficacy of a novel nondepleting anti-CD4 antibody (RIB 5/2) in a model of lung-directed gene therapy in outbred rats. Treatment with RIB 5/2 permitted prolonged reporter gene expression and reduced adenovirus-induced peribronchial and alveolar inflammation in the lung. Moreover administration of RIB 5/2 blocked the development of an anti-adenoviral neutralizing antibody response in the lung and permitted secondary administration and expression of a recombinant adenovirus. These data support the role of immunomodulation in prolonging in vivo transgene expression by recombinant adenovirus.
E1 缺失的腺病毒载体是体细胞基因治疗的有效载体，但转基因表达部分受到针对病毒转导细胞的细胞毒性 T 细胞反应的限制。此外，中和抗体反应的产生限制了这些载体的二次基因转移。用耗竭性抗 CD4 抗体进行治疗可使小鼠肺和肝中的转基因表达延长。此外，CD4+淋巴细胞的短暂耗竭可阻断中和抗体的产生，因此允许重复给药和表达 E1 缺失的重组腺病毒。在本研究中，我们在远交系大鼠的肺定向基因治疗模型中研究了一种新型非耗竭性抗 CD4 抗体（RIB 5/2）的疗效。用 RIB 5/2 治疗可使报告基因表达延长，并减轻肺中腺病毒诱导的支气管周围和肺泡炎症。此外，给予 RIB 5/2 可阻断肺中抗腺病毒中和抗体反应的产生，并允许二次给药和表达重组腺病毒。这些数据支持免疫调节在延长重组腺病毒体内转基因表达中的作用。
