Adenoviral gene delivery elicits distinct pulmonary-associated T helper cell responses to the vector and to its transgene.
Adenoviral gene delivery elicits distinct pulmonary-associated T helper cell responses to the vector and to its transgene.
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DOI：
10.4049/jimmunol.159.2.685
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发表时间：
1997-07
影响因子：
4.4
通讯作者：
F. van Ginkel;J. Mcghee;C. Liu;J. Simecka;M. Yamamoto;R. Frizzell;E. Sorscher;H. Kiyono;D. Pascual
中科院分区：
文献类型：
--
作者：
F. van Ginkel;J. Mcghee;C. Liu;J. Simecka;M. Yamamoto;R. Frizzell;E. Sorscher;H. Kiyono;D. Pascual
复制缺陷型腺病毒 (Ad) 载体可有效特异性靶向呼吸道上皮，用于纠正性基因治疗（如囊性纤维化）或粘膜免疫。作为用 E1/E3 缺失的 Ad5 载体转导下呼吸道的结果，宿主反应的特征在于转基因表达的持续时间和 CTL 反应的诱导。然而，对于了解 CD4+ T 细胞反应对 Ad 载体的贡献的重视有限。在连续气管内 Ad5 转基因滴注后，CD4+ 和 CD8+ T 细胞均迁移至肺部。从肺部分离的 CD3+ T 淋巴细胞主要为 Th2 型，细胞分选后，产生 IL-4 的 T 细胞主要为 CD4+，而 IFN-γ 表达与 CD4+ 和 CD8+ T 细胞相关。对 Ad5 载体和表达的转基因 β-半乳糖苷酶 (β gal) 的 Ab 反应显示，支气管和血清 IgA 和 IgG Ab 升高，中和滴度较低。血清 IgG 亚类反应分析显示，IgG1 和 IgG2b 对 Ad5 的 IgG2a 抗体较低，而 IgG2a 和 IgG2b 对 β gal 的抗体反应较低。 Ad5特异性CD4+T细胞产生Th1（IFN-γ和IL-2）和Th2（IL-4、IL-5、IL-6）型细胞因子，而βgal特异性CD4+T细胞分泌IFN-γ和IL-6。这项研究为Ad5载体在肺全身和粘膜免疫区室中同时诱导Th2型和Th1型反应以及对转基因的Th1型反应提供了直接证据。
Replication-deficient adenovirus (Ad) vectors are effective to specifically target the respiratory epithelium for either corrective gene therapy such as cystic fibrosis or for mucosal immunization. As a consequence of transducing the lower respiratory tract with an E1/E3 deleted Ad5 vector, host responses have been characterized by the duration of transgene expression and by the induction of CTL responses. However, limited emphasis has been devoted to understanding the contribution of CD4+ T cell responses to the Ad vector. Both CD4+ and CD8+ T cells migrate into the lung following sequential intratracheal Ad5 transgene instillations. Isolated CD3+ T lymphocytes from the lungs were predominantly of the Th2 type, and after cell sorting, the IL-4-producing T cells were largely CD4+, while IFN-gamma expression was associated with both CD4+ and CD8+ T cells. Ab responses to the Ad5 vector and to the expressed transgene beta-galactosidase (beta gal) revealed elevated bronchial and serum IgA and IgG Abs with low neutralization titers. Analysis of serum IgG subclass responses showed IgG1 and IgG2b with lower IgG2a Abs to Ad5 and IgG2a and IgG2b Ab responses to beta gal. Ad5-specifc CD4+ T cells produced both Th1 (IFN-gamma and IL-2)- and Th2 (IL-4, IL-5, IL-6)-type cytokines, while beta gal-specific CD4+ T cells secreted IFN-gamma and IL-6. This study provides direct evidence for the concomitant induction of Th2- with Th1-type responses in both the pulmonary systemic and mucosal immune compartments to the Ad5 vector as well as a Th1-dominant response to the transgene.