Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions.
Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions.
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DOI：
10.3389/fimmu.2014.00350
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发表时间：
2014
影响因子：
7.3
通讯作者：
Mingozzi F
中科院分区：
文献类型：
--
作者：
Basner-Tschakarjan E;Mingozzi F
腺相关病毒（AAV）载体是最有效的体内基因传递平台之一。在过去的十年中，AAV载体介导的基因转移的临床试验在基因治疗领域取得了一些最令人兴奋的结果，最近，一种基于AAV的药物在欧洲获得了市场批准。然而，随着临床发展，宿主免疫系统显然是AAV载体成功转移基因的重要障碍。在这篇综述文章中，我们将讨论在人类研究中遇到的针对AAV衣壳的细胞毒性T细胞反应问题。虽然在过去的几年里，该领域已经获得了大量关于AAV载体与免疫系统相互作用的信息，但仍有许多问题没有得到解答。新的概念正在出现，如总衣壳剂量与T细胞介导的转导细胞清除之间的关系，先天免疫在临床前研究中突出的载体免疫原性中的潜在作用，以及调节T细胞和效应T细胞在决定基因转移结果中的相互作用。关于AAV基因转移中的免疫反应还有很多需要了解的地方，例如，目前还不清楚什么是T细胞对载体给予反应的激活动力学的决定因素，为什么不是所有受试者在基因转移后都会产生有害的T细胞反应，以及目前用于阻断T细胞介导的转导细胞清除的干预策略是否对所有基因治疗适应症安全有效。新的临床前模型和临床研究的结果将有助于解决这些问题，并达到开发安全有效的基因治疗方案来治疗人类疾病的重要目标。
Adeno-associated virus (AAV) vectors are one of the most efficient in vivo gene delivery platforms. Over the past decade, clinical trials of AAV vector-mediated gene transfer led to some of the most exciting results in the field of gene therapy and, recently, to the market approval of an AAV-based drug in Europe. With clinical development, however, it became obvious that the host immune system represents an important obstacle to successful gene transfer with AAV vectors. In this review article, we will discuss the issue of cytotoxic T cell responses directed against the AAV capsid encountered on human studies. While over the past several years the field has acquired a tremendous amount of information on the interactions of AAV vectors with the immune system, a lot of questions are still unanswered. Novel concepts are emerging, such as the relationship between the total capsid dose and the T cell-mediated clearance of transduced cells, the potential role of innate immunity in vector immunogenicity highlighted in preclinical studies, and the cross talk between regulatory and effector T cells in the determination of the outcome of gene transfer. There is still a lot to learn about immune responses in AAV gene transfer, for example, it is not well understood what are the determinants of the kinetics of activation of T cells in response to vector administration, why not all subjects develop detrimental T cell responses following gene transfer, and whether the intervention strategies currently in use to block T cell-mediated clearance of transduced cells will be safe and effective for all gene therapy indications. Results from novel preclinical models and clinical studies will help to address these points and to reach the important goal of developing safe and effective gene therapy protocols to treat human diseases.