AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes.
AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes.
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DOI：
10.1038/mtm.2015.29
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Basner-Tschakarjan E
中科院分区：
文献类型：
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作者：
Hui DJ;Edmonson SC;Podsakoff GM;Pien GC;Ivanciu L;Camire RM;Ertl H;Mingozzi F;High KA;Basner-Tschakarjan E
腺相关病毒（AAV）已成为基因转移中最有前途的载体之一，在过去的10年中，成功地翻译为人类的临床试验，甚至在欧洲的第一个基因治疗产品的市场批准。然而，对人类的施用揭示了针对载体衣壳的适应性免疫应答可由于衣壳特异性T细胞的活化和扩增而对持续的转基因表达造成障碍。从临床试验中的样本中获得的外周血单核细胞（PBMC）数量有限，只能用于监测T细胞反应。我们能够确定免疫显性主要组织相容性复合物（MHC）的I类表位的共同人类白细胞抗原（HLA）类型，通过使用脾分离的受试者接受脾切除术的非恶性适应症作为大量的淋巴细胞的来源，并在体外用单一的AAV衣壳肽再刺激它们。进一步的实验证实，这些表位是天然加工的并且功能相关。这些发现促进了更有效和免疫原性更低的AAV载体的设计，以及载体输注受试者的精确免疫监测。
Adeno-associated virus (AAV) has become one of the most promising vectors in gene transfer in the last 10 years with successful translation to clinical trials in humans and even market approval for a first gene therapy product in Europe. Administration to humans, however, revealed that adaptive immune responses against the vector capsid can present an obstacle to sustained transgene expression due to the activation and expansion of capsid-specific T cells. The limited number of peripheral blood mononuclear cells (PBMCs) obtained from samples within clinical trials allows for little more than monitoring of T-cell responses. We were able to identify immunodominant major histocompatibility complex (MHC) class I epitopes for common human leukocyte antigen (HLA) types by using spleens isolated from subjects undergoing splenectomy for non-malignant indications as a source of large numbers of lymphocytes and restimulating them with single AAV capsid peptides in vitro. Further experiments confirmed that these epitopes are naturally processed and functionally relevant. The design of more effective and less immunogenic AAV vectors, and precise immune monitoring of vector-infused subjects, are facilitated by these findings.