Kapturczak M H, Flotte T, Atkinson M A
Department of Medicine, University of Florida, Gainesville 32610, USA.
Curr Mol Med. 2001 May;1(2):245-58. doi: 10.2174/1566524013363979.
Most viral gene delivery syslems utilized to date have demonstrated significant limitations in practicality and safety due to the level and duration of recombinant transgene expression as well as their induction of host immunogenicity to vector proteins. Recombinant adeno-associated virus (rAAV) vectors appear to offer a vehicle for safe, long-term therapeutic gene transfer; factors afforded through the propensity of rAAV to establish long-term latency without deleterious effects on the host cell and the relative non-immunogenicity of the virus or viral expressed transgenes. The principal historical limitation of this vector system, efficiency of rAAV-mediated transduction, has recently observed a dramatic increase as the titer, purity, and production capacity of rAAV preparations have improved. In terms of systems that could benefit from such improvements, rAAV gene therapy to enhance solid organ transplantation would appear an obvious choice with islet transplantation forming a promising candidate due to the ability to perform viral transductions ex vivo. Currently, islet transplantation can be used to treat type 1 diabetes yet persisting alloimmune and autoimmune responses represent major obstacles to the clinical success for this procedure. The delivery of transgenes capable of interfering with antigenic recognition and/or cell death [e.g., Fas ligand (FasL), Bcl-2, Bcl-XL] as well as imparting tolerance/immunoregulation [e.g., interleukin(IL)-4, IL-10, transforming growth factor (TGF)-beta], or cytoprotection [e.g., heme oxygenase-1 (HO-1), catalase, manganese superoxide dismutase (MnSOD)] may prevent recurrent type 1 diabetes in islet transplantation and offer a promising form of immunotherapy. Research investigations utilizing such systems may also provide information vital to understanding the immunoregulatory mechanisms critical to the development of both alloimmune and autoimmune islet cell rejection mechanisms and recurrent type 1 diabetes.
迄今为止，由于重组转基因表达的水平和持续时间以及它们对载体蛋白诱导宿主免疫原性，大多数已使用的病毒基因递送系统在实用性和安全性方面已显示出显著局限性。重组腺相关病毒（rAAV）载体似乎为安全、长期的治疗性基因转移提供了一种载体；rAAV具有建立长期潜伏性而对宿主细胞无有害影响的倾向，以及病毒或病毒表达的转基因相对无免疫原性，这些因素为其提供了优势。该载体系统主要的历史局限性，即rAAV介导的转导效率，最近随着rAAV制剂的滴度、纯度和生产能力的提高而显著提高。就可能受益于此类改进的系统而言，增强实体器官移植的rAAV基因治疗似乎是一个明显的选择，由于能够在体外进行病毒转导，胰岛移植成为一个有前景的候选对象。目前，胰岛移植可用于治疗1型糖尿病，但持续存在的同种免疫和自身免疫反应是该手术临床成功的主要障碍。递送能够干扰抗原识别和/或细胞死亡的转基因[例如，Fas配体（FasL）、Bcl-2、Bcl-XL]以及赋予耐受性/免疫调节[例如，白细胞介素（IL）-4、IL-10、转化生长因子（TGF）-β]或细胞保护作用[例如，血红素加氧酶-1（HO-1）、过氧化氢酶、锰超氧化物歧化酶（MnSOD）]可能预防胰岛移植中复发性1型糖尿病，并提供一种有前景的免疫治疗形式。利用此类系统的研究调查也可能提供对于理解同种免疫和自身免疫胰岛细胞排斥机制以及复发性1型糖尿病发展至关重要的免疫调节机制的关键信息。
