Induction of immunity to antigens expressed by recombinant adeno-associated virus depends on the route of administration
Induction of immunity to antigens expressed by recombinant adeno-associated virus depends on the route of administration
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DOI：
10.1006/clim.1999.4724
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发表时间：
1999-07-01
影响因子：
8.6
通讯作者：
Engleman, EG
中科院分区：
文献类型：
--
作者：
Brockstedt, DG;Podsakoff, GM;Engleman, EG
重组腺相关病毒(RAAV)是一种复制缺陷的细小病毒，因其宿主范围广、安全性好、转基因在受感染宿主中持续表达而被开发为基因治疗的载体。几个研究小组也报道，rAAV对其编码的转基因产物几乎没有或几乎没有诱导免疫反应。本研究通过研究C57BL/6小鼠对不同途径单剂rAAV编码卵清蛋白(AAV-OVA)的免疫应答，重新检测了rAAV的免疫原性。腹膜内(IP)、静脉或皮下注射AAV-OVA的小鼠可产生强大的卵清蛋白特异性细胞毒性T淋巴细胞(CTL)以及抗卵白蛋白抗体和AAV抗体，相比之下，肌肉注射AAV-OVA的小鼠对病毒和转基因小鼠产生体液反应，但极少量的卵清蛋白特异性CTL。IP注射AAV-OVA后诱导的CTL反应可保护小鼠免受随后的卵蛋白转基因B16黑色素瘤细胞株的肿瘤攻击。对AAV-OVA诱导CTL机制的研究证实，该病毒将转基因产物送入经典的MHC-I类抗原处理途径。以前接触过rAAV载体的小鼠在注射AAV-OVA后未能产生卵清蛋白特异的CTL，对这些小鼠的分析显示，循环中存在抗AAV抗体，在体外阻断rAAV的转导，并抑制体内CTL的诱导，这些结果表明rAAV在恶性肿瘤和病毒感染的免疫治疗中可能发挥作用，尽管对AAV的诱导抗体应答可能限制其重复接种的能力。(C)1999年学术出版社。
Recombinant adeno-associated virus (rAAV) is a replication-defective parvovirus which is being explored as a vector for gene therapy because of its broad host range, excellent safety profile, and durable transgene expression in infected hosts. rAAV has also been reported by several groups to induce little or no immune response to its encoded transgene products. In this study Re examined the immunogenicity of rAAV by studying the immune response of C57BL/6 mice to a single dose of rAAV-encoding ovalbumin (AAV-Ova) administered by a variety of routes. Mice injected with AAV-Ova intraperitoneally (ip), intravenously, or subcutaneously developed potent ovalbumin-specific cytotoxic T lymphocytes (CTL) as well as anti-ovalbumin antibodies and antibodies to AAV, In contrast, mice injected with AAV-Ova intramuscularly developed a humoral response to the virus and the transgene but minimal ovalbumin-specific CTLs. The induced CTL response after ip administration of AAV-Ova protected mice against a subsequent tumor challenge with an ovalbumin-transfected B16 melanoma cell line. Studies of the mechanism by which AAV-Ova induces CTL confirmed that the virus; delivers the transgene product into the classical MHC class I pathway of antigen processing. Mice that previously had been exposed to rAAV vectors failed to develop ovalbumin-specific CTL following administration of AAV-Ova, Analysis of these mice revealed the presence of circulating anti-AAV antibodies that blocked rAAV transduction in vitro and inhibited CTL induction in vivo, These results suggest a possible role for rAAV in the immunotherapy of malignancies and viral infections, although induced antibody responses to AAV may limit its ability to be administered for repeated vaccinations. (C) 1999 Academic Press.