Smith C A, Woodruff L S, Rooney C, Kitchingman G R
Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, TN 38101, USA.
Hum Gene Ther. 1998 Jul 1;9(10):1419-27. doi: 10.1089/hum.1998.9.10-1419.
Although adenovirus is a major source of morbidity for immunocompromised individuals and a popular vector for gene therapy, little is known about the cellular immune responses it evokes in humans. Initial trials using adenovirus vectors have been disappointing, probably owing both to a preexisting immune response to Ad2 and Ad5, the most commonly used vector backbones, and to a response to the transgene. The former problem might be overcome by switching from the common type C adenoviruses, of which Ad2 and Ad5 are members, to other less common serotypes. Evidence for the feasibility of this approach has been provided by a rat model system. However, its success in humans depends on there being no immunological cross-reactivity between groups at the humoral or cellular level. Here, we examine the cross-reactivity of the cellular immune response to adenovirus in a human system, and find that human cytotoxic T lymphocytes (CTLs) prepared in vitro against an adenovirus from two of the six subgroups can lyse cells infected with adenoviruses from the other subgroups. Hence, the proposed use of adenovirus vectors from uncommon subgroups to evade memory immune response to subgroup C adenoviruses may not be successful. However, this same cross-reactivity indicates that adoptive transfer of CTLs generated in vitro against one adenovirus serotype may protect immunocompromised patients from infections by adenoviruses of all serotypes.
尽管腺病毒是免疫功能低下个体发病的主要原因，也是基因治疗常用的载体，但人们对其在人类中引发的细胞免疫反应知之甚少。使用腺病毒载体的初步试验令人失望，这可能是由于对最常用的载体骨架Ad2和Ad5存在预先存在的免疫反应，以及对转基因的反应。前一个问题可以通过从常见的C型腺病毒（Ad2和Ad5属于此类）转向其他不太常见的血清型来克服。大鼠模型系统已经为这种方法的可行性提供了证据。然而，它在人类中的成功取决于在体液或细胞水平上不同组之间不存在免疫交叉反应。在这里，我们在人类系统中研究了对腺病毒细胞免疫反应的交叉反应性，发现体外制备的针对六个亚组中两个亚组腺病毒的人类细胞毒性T淋巴细胞（CTL）可以裂解感染其他亚组腺病毒的细胞。因此，提议使用不常见亚组的腺病毒载体来逃避对C亚组腺病毒的记忆免疫反应可能不会成功。然而，同样的交叉反应性表明，体外产生的针对一种腺病毒血清型的CTL的过继转移可能会保护免疫功能低下的患者免受所有血清型腺病毒的感染。
