Kushwah Rahul, Cao Huibi, Hu Jim
Physiology and Experimental Medicine Research Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
J Immunol. 2008 Mar 15;180(6):4098-108. doi: 10.4049/jimmunol.180.6.4098.
In spite of the extensive research in the field of gene therapy, host immune responses continue to be the major barrier in translating basic research to clinical practice. Helper-dependent adenoviral (HD-Ad) vectors show great potential for pulmonary gene therapy, but the knowledge of pulmonary immune responses toward these vectors is very limited. In this study, we show that HD-Ad vectors are potent stimulators of dendritic cell (DC) maturation, thus leading to stimulation of T cell proliferation with approximately 6% of naive CD4(+) T cells from pulmonary mediastinal lymph node responding to HD-Ad-treated DCs. In contrast to the belief that HD-Ad vectors are unable to prime adaptive immune response, we show for the first time, through in vivo pulmonary studies in mice, that HD-Ad vectors can prime CD4(+) and CD8(+) T cell responses in the lung at high and substantially low doses. This indicates cross-presentation of HD-Ad-derived epitopes by DCs to prime CD8(+) T cell responses. To assess the basis of pulmonary T cell response against HD-Ad vectors, we examined the response of conventional DCs (cDCs) and plasmacytoid DCs (pDCs) in the lung. In response to HD-Ad delivery, there is induction of maturation in both cDC and pDC subsets, but it is the cDCs, not pDCs, that migrate rapidly to draining lymph nodes within the first 2 days after vector delivery to prime adaptive immune response against these vectors. These findings have implications for development of strategies to prevent adaptive immune responses against gene therapy vectors.
尽管在基因治疗领域进行了广泛研究，但宿主免疫反应仍然是基础研究转化为临床实践的主要障碍。辅助依赖型腺病毒（HD-Ad）载体在肺部基因治疗中显示出巨大潜力，但关于肺部对这些载体的免疫反应的了解非常有限。在本研究中，我们表明HD-Ad载体是树突状细胞（DC）成熟的有效刺激物，从而导致T细胞增殖受到刺激，来自肺纵隔淋巴结的约6%的初始CD4(+) T细胞对经HD-Ad处理的DC作出反应。与认为HD-Ad载体无法引发适应性免疫反应的观点相反，我们首次通过对小鼠的体内肺部研究表明，HD-Ad载体在高剂量和极低剂量下均可在肺部引发CD4(+)和CD8(+) T细胞反应。这表明DC对HD-Ad衍生表位进行交叉呈递以引发CD8(+) T细胞反应。为了评估肺部针对HD-Ad载体的T细胞反应的基础，我们检测了肺部常规DC（cDC）和浆细胞样DC（pDC）的反应。响应HD-Ad递送，cDC和pDC亚群均发生成熟诱导，但在载体递送后的头2天内迅速迁移至引流淋巴结以引发针对这些载体的适应性免疫反应的是cDC，而非pDC。这些发现对开发预防针对基因治疗载体的适应性免疫反应的策略具有启示意义。
