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重组腺相关病毒(rAAV)已成为基因治疗领域应用最广泛的载体之一。临床前研究显示其具有很高的安全性,但人体免疫毒性仍是制约其临床疗效的关键,因此有关rAAV免疫机制的研究成为近期热点。尽管天然免疫在获得性免疫反应中发挥重要作用,但与rAAV有关的天然免疫研究过去一直未被重视。直到最近,才确认有至少3种人体细胞(树突状细胞、巨噬细胞和内皮细胞)参与了rAAV的天然免疫,作用机制为可识别载体基因组的TLR9或病毒衣壳TLR2所介导,NF-κB或干扰素调节因子(IRFs)信号通路被激活,导致各种炎性因子及I型干扰素的大量表达。自身互补型rAAV诱导的TLR9依赖性天然免疫较单链rAAV更为强烈。本文重点对近期发现的激活天然免疫反应的宿主与rAAV的相互作用、涉及的信号通路、天然免疫对获得性免疫以及转基因表达的影响进行综述。
Recombinant adeno-associated virus (rAAV) has become one of the most widely used vectors in gene therapy. Preclinical studies have shown that it has a high safety, but human immunotoxicity is still the key to restrict its clinical efficacy, so the research on the mechanism of rAAV immunization has become a hot spot recently. Although innate immunity plays an important role in the adaptive immune response, natural immune research related to rAAV has not been valued in the past. Until recently, it has been confirmed that at least 3 human cells (dendritic cells, macrophages, and endothelial cells) are involved in innate immunity to rAAV mediated by TLR9 recognizing the vector genome or TLR2, a viral envelope -κB or interferon regulatory factor (IRFs) signaling pathway is activated, resulting in the expression of various inflammatory cytokines and type I interferons. Self-complementary rAAV-induced TLR9-dependent innate immunity is more intense than single-chain rAAV. This review focuses on the recent discovery of the interaction of host-activated rAAV with the innate immune response involved, the signaling pathways involved, and the effects of innate immunity on acquired immunity and transgene expression.