Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94103-0555, USA.
Mol Ther. 2013 Jan;21(1):158-66. doi: 10.1038/mt.2012.167. Epub 2012 Aug 28.
There is considerable interest in the use of adeno-associated virus serotype 9 (AAV9) for neurological gene therapy partly because of its ability to cross the blood-brain barrier to transduce astrocytes and neurons. This raises the possibility that AAV9 might also transduce antigen-presenting cells (APC) in the brain and provoke an adaptive immune response. We tested this hypothesis by infusing AAV9 vectors encoding foreign antigens, namely human aromatic L-amino acid decarboxylase (hAADC) and green fluorescent protein (GFP), into rat brain parenchyma. Over ensuing weeks, both vectors elicited a prominent inflammation in transduced brain regions associated with upregulation of MHC II in glia and associated lymphocytic infiltration. Transduction of either thalamus or striatum with AAV9-hAADC evinced a significant loss of neurons and induction of anti-hAADC antibodies. We conclude that AAV9 transduces APC in the brain and, depending on the immunogenicity of the transgene, can provoke a full immune response that mediates significant brain pathology. We emphasize, however, that these observations do not preclude the use of AAV serotypes that can transduce APC. However, it does potentially complicate preclinical toxicology studies in which non-self proteins are expressed at a level sufficient to trigger cell-mediated and humoral immune responses.
人们对使用腺相关病毒血清型 9（AAV9）进行神经基因治疗非常感兴趣，部分原因是它能够穿透血脑屏障转导星形胶质细胞和神经元。这就提出了一个可能性，即 AAV9 也可能转导大脑中的抗原呈递细胞（APC）并引发适应性免疫反应。我们通过将编码外源抗原的 AAV9 载体（即人芳香族 L-氨基酸脱羧酶（hAADC）和绿色荧光蛋白（GFP））注入大鼠脑实质来检验这一假说。在接下来的几周内，两种载体都在转导的脑区引起了明显的炎症，伴有胶质细胞中 MHC II 的上调和相关的淋巴细胞浸润。用 AAV9-hAADC 转导丘脑或纹状体，可明显导致神经元丢失和抗 hAADC 抗体的诱导。我们的结论是，AAV9 可转导大脑中的 APC，并且根据转基因的免疫原性，可能引发全面的免疫反应，从而介导明显的脑病理。然而，我们强调，这些观察结果并不排除使用能够转导 APC 的 AAV 血清型。然而，它确实可能使非自身蛋白在足以引发细胞和体液免疫反应的水平上表达的临床前毒理学研究变得复杂。
