Transient immune blockade prevents formation of neutralizing antibody to recombinant adenovirus and allows repeated gene transfer to mouse liver.
Transient immune blockade prevents formation of neutralizing antibody to recombinant adenovirus and allows repeated gene transfer to mouse liver.
复制标题
瞬时免疫阻断可防止重组腺病毒中和抗体的形成，并允许将基因重复转移至小鼠肝脏。
作者：
Yiping Yang;K. Greenough;James M. Wilson
人腺病毒的亲肝特性已经被用来开发体内肝脏导向基因治疗的载体。目前这种载体系统的局限性是由于抗原特异性细胞免疫反应而发展成的相关性肝炎，以及实现重复基因转移的困难。这项研究使用小鼠模型来定义受体动物的免疫反应，这些免疫反应以前已经被证明可以防止病毒成功地重新注射，并提出了防止这些阻断免疫反应发展的方法。我们的研究与第二类MHC依赖的T辅助细胞和B细胞对输入病毒衣壳蛋白的激活最一致，导致在初次接触病毒后产生抗病毒中和抗体；这种衣壳特异性抗体似乎与病毒结合，并防止第二次注射病毒的情况下进入。在注射病毒时瞬间去除CD4功能可防止中和抗体的形成，从而在随后至少两次注射病毒后进行有效的基因转移。在用IL-12治疗的Beta(2)m(-)小鼠和C57BL/6小鼠上的实验表明，基于抑制T辅助T细胞的T(H2)亚群的激活，可以更有选择性地消融免疫功能。从这些关于免疫机制的研究中，希望能够开发出可行的策略来克服最初的基因治疗后出现的体液免疫问题。
The hepatotropic properties of human adenoviruses have been used to develop vectors for in vivo liver-directed gene therapy. Current limitations for this vector system are the associated hepatitis that develops as a result of antigen-specific cellular immune responses and the difficulty in accomplishing repeated gene transfer. This study uses mouse models to define immune responses of the recipient animal that have previously been shown to prevent successful re-administration of virus and suggests approaches for preventing the development of these blocking immune responses. Our studies are most consistent with class II MHC-dependent activation ot T helper cells and B cells to capsid proteins of the input virus leading to the production of antiviral neutralizing antibody following a primary exposure to virus; this capsid-specific antibody appears to bind to virus and prevents entry in the context of a second administration of virus. Transient ablation of CD4 function at the time of virus administration prevents the formation of neutralizing antibody thereby allowing efficient gene transfer after at least two subsequent administrations of virus. Experiments in beta(2)m(-) mice and C57BL/6 mice treated with IL-12 suggested a more selective ablation of immune function based on inhibiting the activation of the T(H2) subset of T helper cells. From these studies on immune mechanisms it is hoped that viable strategies can be developed to overcome the problem of humoral immunity that occurs after the initial genetic therapy.