Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunity
Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunity
复制标题
对腺相关病毒血清型 2 传递的转基因的免疫力是由自身免疫遗传倾向赋予的
作者：
Ying Zhang;Matthew Powers;C. Wasserfall;T. Brusko;Sihong Song;Terence R. Flotte;Richard O. Snyder;Mark Potter;Marda Scott;M. Campbell;James M. Crawford;Harry S. Nick;A. Agarwal;T. Ellis;Mark A. Atkinson
腺相关病毒（Adeno-associated virus，AAV）是一种很有前途的基因治疗载体。这一承诺是基于以前的研究评估AAV的安全性和毒性，感染非分裂细胞的能力，引发有限的免疫反应，并提供长期的基因表达。然而，我们现在发现，早期的研究低估了AAV免疫原性的程度以及遗传背景通过调节免疫应答影响基因表达持续时间从而影响AAV介导的基因治疗的有效性的程度。我们评估了12种小鼠品系对AAV血清型2（AAV 2）和AAV 2表达的转基因产物（包括绿色荧光蛋白（GFP）、人α1-抗胰蛋白酶和鼠白细胞介素-10）的抗体应答。正如预期的，施用AAV 2的所有免疫活性小鼠都产生了对病毒的免疫应答性的血清学证据。然而，观察到先前未鉴定的血清学前带效应，表明抗AAV 2抗体的浓度可能在历史上被显著低估。此外，具有自身免疫性遗传倾向的菌株（例如，NOD、NZW、MRL-1 pr）特异性地赋予AAV递送的转基因产物功能上有害的免疫应答。这些发现表明，应进行更彻底的抗AAV免疫研究，并且在评估AAV在人体中的疗效和安全性时应考虑自身免疫的遗传易感性。
Adeno-associated virus (AAV) is widely considered a promising vector for therapeutic gene delivery. This promise is based on previous studies assessing AAVs safety and toxicity, ability to infect nondividing cells, elicit a limited immune response and provide long-term gene expression. However, we now find that earlier studies underappreciated the degree of AAV immunogenicity as well as the extent to which genetic background, through regulation of immune responsiveness, influences the duration of gene expression and thereby the effectiveness of AAV-mediated gene therapy. We evaluated antibody responses in 12 mouse strains to AAV serotype 2 (AAV2) and AAV2-expressed transgene products including green fluorescent protein (GFP), human α1-antitrypsin and murine interleukin-10. As expected, all immunocompetent mice administered AAV2 developed serologic evidence of immune responsiveness to the virus. However, a previously unidentified serologic prozone effect was observed suggesting that the concentrations of anti-AAV2 antibodies may have historically been subject to marked underestimation. Furthermore, strains with genetic predisposition to autoimmunity (eg, NOD, NZW, MRL-lpr) specifically imparted a functionally deleterious immune response to AAV-delivered transgene products. These findings suggest that more thorough studies of anti-AAV immunity should be performed, and that genetic predisposition to autoimmunity should be considered when assessing AAV efficacy and safety in humans.
影响因子：
8.6
作者：
Brockstedt, DG;Podsakoff, GM;Engleman, EG
通讯作者：
Engleman, EG
给药途径决定了对腺相关病毒载体的 T 细胞依赖性体液反应的诱导。
DOI：
10.1006/mthe.2000.0045
发表时间：
2000
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy.
影响因子：
--
作者：
Xiao,W;Chirmule,N;Schnell,MA;Tazelaar,J;Hughes,JV;Wilson,JM
通讯作者：
Wilson,JM
重组腺相关病毒介导的视网膜转导后体内报告基因表达的跨物种比较。
影响因子：
--
作者：
Bennett,J;Anand,V;Acland,GM;Maguire,AM
通讯作者：
Maguire,AM