Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
Curr Pharm Des. 2011;17(24):2542-9. doi: 10.2174/138161211797247604.
Hepatocytes are a key target for gene transfer directed at correction of inborn errors of metabolism. The theoretical potential of hepatocyte-directed gene transfer contrasts with the hurdles for clinical translation of this technology. Innate immune responses following gene transfer are initiated by recognition of pathogen-associated molecular patterns by pattern recognition receptors like Toll-like receptors. Adaptive immune responses may constitute the most significant hurdle for efficient gene transfer. Besides the challenge imposed by adaptive immune responses against the vector and the potential problem of pre-existing immunity, immune responses against the transgene product may also constitute an obstacle. The liver is a tolerogenic organ. Naive T cells encounter liver antigens initially in the liver, rather than in lymphoid tissue. Lymph nodes and the spleen are anatomical compartments that provide a particular microarchitecture and microenvironment for the induction of immunity. In contrast, antigen presentation in the liver takes place in a completely different microarchitecture and microenvironment. This is a key aspect of the hepatic adaptive immune tolerance induction. Consistent with the tolerogenic nature of the liver microenvironment, the risk of antibody formation against the transgene product may be limited in the setting of hepatocyte-directed gene transfer and specifically by restricting transgene expression to hepatocytes by use of hepatocyte-specific expression cassettes. However, it is unclear to which extent animal experimental data following gene transfer predict immune responses in humans. Extrapolations from animals to humans are required but should be performed with sufficient insight into the dramatic species differences of the immune system.
肝细胞是基因转移纠正先天性代谢错误的主要靶标。肝细胞定向基因转移的理论潜力与该技术向临床转化的障碍形成鲜明对比。基因转移后固有免疫反应是由模式识别受体（如 Toll 样受体）识别病原体相关分子模式引发的。适应性免疫反应可能是高效基因转移的最大障碍。除了针对载体的适应性免疫反应带来的挑战和潜在的预先存在的免疫问题外，针对转基因产物的免疫反应也可能构成障碍。肝脏是一个耐受器官。幼稚 T 细胞最初在肝脏而不是在淋巴组织中遇到肝脏抗原。淋巴结和脾脏是为诱导免疫提供特定的微结构和微环境的解剖学隔间。相比之下，肝脏中的抗原呈递发生在完全不同的微结构和微环境中。这是肝脏适应性免疫耐受诱导的一个关键方面。与肝脏微环境的耐受性质一致，针对转基因产物形成抗体的风险可能在肝细胞定向基因转移的情况下受到限制，特别是通过使用肝细胞特异性表达盒将转基因表达限制在肝细胞中。然而，基因转移后动物实验数据对人类免疫反应的预测程度尚不清楚。需要从动物到人类的推断，但应该对免疫系统的巨大种间差异有足够的了解。
