炎症促进腺相关病毒介导的转基因在小鼠肝脏中的表达丢失。
Inflammation promotes the loss of adeno-associated virus-mediated transgene expression in mouse liver.
机构信息
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-3403, USA.
出版信息
Gastroenterology. 2011 Jul;141(1):348-57, 357.e1-3. doi: 10.1053/j.gastro.2011.04.002. Epub 2011 Apr 12.
Abstract
BACKGROUND & AIMS: Non-self transgenes delivered to mouse liver via adeno-associated virus (AAV) are expressed stably due to the induction of immune tolerance. However, such transgene expression has been reported to be lost in higher-order primates. We investigated whether inflammatory processes, which likely differ between species, impact the stability of transgene expression.
METHODS
We developed a mouse model that mimics a scenario in which a subject that has received hepatic AAV-mediated gene transfer develops subsequent, vector-unrelated, systemic inflammation.
RESULTS
Inflammation eliminated previously stable expression of transgenes delivered by AAV; the limited tissue destruction and persistence of AAV genomes implicated pathways besides the cytotoxic T-cell response. Tumor necrosis factor-a down-regulated expression of the transgene from the AAV, indicating a role for similar inflammatory cytokines in such loss of transgene expression.
CONCLUSIONS
Inflammation can block AAV-mediated expression of transgenes in mouse liver. The presence of inflammation might therefore affect hepatic expression of transgenes from viral vectors in humans.
摘要
背景与目的
腺相关病毒（AAV）介导的非自身转基因递送至小鼠肝脏后，由于诱导免疫耐受而稳定表达。然而，据报道，在高等灵长类动物中，这种转基因的表达会丢失。我们研究了炎症过程是否会影响转基因表达的稳定性，因为不同物种之间的炎症过程可能存在差异。
方法
我们开发了一种小鼠模型，模拟了接受肝 AAV 介导的基因转移的个体随后发生与载体无关的全身炎症的情况。
结果
炎症消除了先前由 AAV 传递的转基因的稳定表达；有限的组织破坏和 AAV 基因组的持续存在暗示了除细胞毒性 T 细胞反应之外的途径。肿瘤坏死因子-α下调了 AAV 中转基因的表达，表明类似的炎症细胞因子在这种转基因表达的丧失中起作用。
结论
炎症可以阻断 AAV 介导的小鼠肝脏中转基因的表达。因此，炎症的存在可能会影响人类病毒载体中转基因在肝脏中的表达。
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