Hepatic gene transfer as a means of tolerance induction to transgene products.
Hepatic gene transfer as a means of tolerance induction to transgene products.
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DOI：
10.2174/156652309787909490
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发表时间：
2009-04
影响因子：
3.6
通讯作者：
Herzog RW
中科院分区：
文献类型：
--
作者：
LoDuca PA;Hoffman BE;Herzog RW
肝脏是基因治疗的首选靶器官，不仅适用于肝脏特异性疾病，而且适用于需要全身输送蛋白质的疾病。可以从肝脏基因转移中获益的疾病包括血友病、代谢紊乱、溶酶体贮积症等。为了成功传递转基因并持续表达，该方案必须避免免疫反应才能有效。越来越多的研究表明，肝脏定向转移可以诱导转基因产物特异性免疫耐受。通过这种途径获得的耐受性需要对载体进行优化设计，以消除抗原呈递细胞中的转基因表达，同时限制肝细胞的高水平治疗表达。先天免疫反应可能会阻止耐受诱导，引起毒性，因此必须尽量减少。我们的综述讨论了 CD4+CD25+ 调节性 T 细胞在肝细胞源性基因产物耐受中的关键作用、肝脏的免疫生物学和我们目前对其耐受特性的理解、关于肝脏独特细胞环境背后机制的当前和拟议研究，以及耐受诱导工具（如先进载体系统）的开发。
The liver is a preferred target organ for gene therapy not only for liver-specific diseases but also for disorders that require systemic delivery of a protein. Diseases that could benefit from hepatic gene transfer include hemophilia, metabolic disorders, lysosomal storage disorders, and others. For a successful delivery of the transgene and sustained expression, the protocol must avoid immune responses in order to be efficacious. A growing number of studies have demonstrated that liver-directed transfer can induce transgene product-specific immune tolerance. Tolerance obtained via this route requires optimal engineering of the vector to eliminate transgene expression in antigen presenting cells while restricting high levels of therapeutic expression to hepatocytes. Innate immune responses may prevent tolerance induction, cause toxicity, and have to be minimized. Discussed in our review is the crucial role of CD4+CD25+ regulatory T cells in tolerance to the hepatocyte-derived gene product, the immunobiology of the liver and our current understanding of its tolerogenic properties, current and proposed research as to the mechanisms behind the liver’s unique cellular environment, as well as development of the tools for tolerance induction such as advanced vector systems.
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