AAV9-mediated Expression of a Non-self Protein in Nonhuman Primate Central Nervous System Triggers Widespread Neuroinflammation Driven by Antigen-presenting Cell Transduction
AAV9-mediated Expression of a Non-self Protein in Nonhuman Primate Central Nervous System Triggers Widespread Neuroinflammation Driven by Antigen-presenting Cell Transduction
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DOI：
10.1038/mt.2013.266
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发表时间：
2014-02-01
影响因子：
12.4
通讯作者：
Bankiewicz, Krystof S.
中科院分区：
文献类型：
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作者：
Samaranch, Lluis;Sebastian, Waldy San;Bankiewicz, Krystof S.
许多研究表明，腺相关病毒血清型9（AAV 9）转导星形胶质细胞和神经元时，注入大鼠或非人灵长类动物（NHP）的大脑。我们先前在大鼠中表明，编码外源蛋白的AAV 9转导抗原呈递细胞（APC）引发了完全的神经毒性免疫反应。因此，我们询问这种现象是否发生在NHR中。我们在单独的NHR中进行了编码绿色荧光蛋白（GFP）（一种来源于水母的非自身蛋白）或人芳香族L-氨基酸脱羧酶（hAADC）（一种自身蛋白）的AAV 9的实质或鞘内输注。将AAV 9-GFP接受到小脑延髓池（CM）中的动物变得共济失调，表明小脑病理学，而AAV 9-hAADC动物保持健康。在转导区域，AAV 9-GFP引起与星形胶质细胞和小胶质细胞的早期活化相关的炎症，沿着胶质细胞中主要组织相容性复合体II类（MHC-II）的上调。此外，我们发现浦肯野神经元在AAV 9-GFP递送后缺乏钙结合蛋白，但在AAV 9-hAADC递送后没有。我们的研究结果表明，AAV 9介导的外源蛋白的表达，而不是自我识别的蛋白质，触发完整的免疫反应，在NHP，无论给药途径。我们的研究结果值得谨慎时，考虑使用血清型，可以antiAPC，如果转基因是不同源的主机。这一发现有可能使临床前毒理学研究复杂化，其中在动物中测试编码人cDNA的这种载体。
Many studies have demonstrated that adeno-associated virus serotype 9 (AAV9) transduces astrocytes and neurons when infused into rat or nonhuman primate (NHP) brain. We previously showed in rats that transduction of antigen-presenting cells (APC) by AAV9 encoding a foreign protein triggered a full neurotoxic immune response. Accordingly, we asked whether this phenomenon occurred in NHR We performed parenchymal or intrathecal infusion of AAV9 encoding green fluorescent protein (GFP), a nonself protein derived from jellyfish, or human aromatic L-amino acid decarboxylase (hAADC), a self-protein, in separate NHR Animals receiving AAV9-GFP into cisterna magna (CM) became ataxic, indicating cerebellar pathology, whereas AAV9-hAADC animals remained healthy. In transduced regions, AAV9-GFP elicited inflammation associated with early activation of astrocytic and microglial cells, along with upregulation of major histocompatibility complex class ll (MHC-II) in glia. In addition, we found Purkinje neurons lacking calbindin after AAV9-GFP but not after AAV9-hAADC delivery. Our results demonstrate that AAV9-mediated expression of a foreign-protein, but not self-recognized protein, triggers complete immune responses in NHP regardless of the route of administration. Our results warrant caution when contemplating use of serotypes that can transduce APC if the transgene is not syngeneic with the host. This finding has the potential to complicate preclinical toxicology studies in which such vectors encoding human cDNA's are tested in animals.