Connors M, Giese N A, Kulkarni A B, Firestone C Y, Morse H C, Murphy B R
Respiratory Viruses Section, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
J Virol. 1994 Aug;68(8):5321-5. doi: 10.1128/JVI.68.8.5321-5325.1994.
In previous studies, children immunized with a formalin-inactivated respiratory syncytial virus vaccine (FI-RSV) developed severe pulmonary disease with greater frequency than did controls during subsequent natural RSV infection. In earlier efforts to develop an animal model for this phenomenon, extensive pulmonary histopathology developed in FI-RSV-immunized cotton rats and mice subsequently challenged with RSV. In mice, depletion of CD4+ T cells at the time of RSV challenge completely abrogated this histopathology. Furthermore, the predominant cytokine mRNA present in lungs of FI-RSV-immunized mice during subsequent infection with RSV was that characteristically secreted by Th2 T cells, namely interleukin-4 (IL-4). In the present studies, we sought to determine the relative contributions of gamma interferon (IFN-gamma), IL-2, IL-4, and IL-10 to the lymphocytic infiltration into the lungs observed following RSV challenge of mice previously immunized with FI-RSV. Mice previously immunized with FI-RSV or infected with RSV were depleted of IFN-gamma, IL-2, IL-4, or IL-10 immediately before RSV challenge, and the magnitude of inflammatory cell infiltration around bronchioles and pulmonary blood vessels was quantified. The phenomenon of pulmonary-histopathology potentiation by FI-RSV was reproduced in the present study, thereby allowing us to investigate the effect of cytokine depletion on the process. Simultaneous depletion of both IL-4 and IL-10 completely abrogated pulmonary histopathology in FI-RSV-immunized mice. Depletion of IL-4 alone significantly reduced bronchiolar, though not perivascular, histopathology. Depletion of IL-10 alone had no effect. Depletion of IFN-gamma, IL-2, or both together had no effect on the observed histopathology. These data indicate that FI-RSV immunization primes for a Th2-, IL-4-, and IL-10-dependent inflammatory response to subsequent RSV infection. It is possible that this process played a role in enhanced disease observed in infants and children immunized with FI-RSV.
在先前的研究中，接种福尔马林灭活呼吸道合胞病毒疫苗（FI-RSV）的儿童在随后自然感染呼吸道合胞病毒（RSV）期间，发生严重肺部疾病的频率高于对照组。在早期为这一现象建立动物模型的研究中，接种FI-RSV的棉鼠和小鼠在随后受到RSV攻击后出现了广泛的肺部组织病理学变化。在小鼠中，RSV攻击时CD4+T细胞的耗竭完全消除了这种组织病理学变化。此外，在接种FI-RSV的小鼠随后感染RSV期间，肺中存在的主要细胞因子mRNA是Th2 T细胞典型分泌的，即白细胞介素-4（IL-4）。在本研究中，我们试图确定γ干扰素（IFN-γ）、IL-2、IL-4和IL-10对先前接种FI-RSV的小鼠受到RSV攻击后观察到的肺部淋巴细胞浸润的相对贡献。先前接种FI-RSV或感染RSV的小鼠在RSV攻击前立即耗竭IFN-γ、IL-2、IL-4或IL-10，并对细支气管和肺血管周围的炎症细胞浸润程度进行定量。本研究重现了FI-RSV增强肺部组织病理学的现象，从而使我们能够研究细胞因子耗竭对这一过程的影响。同时耗竭IL-4和IL-10完全消除了接种FI-RSV小鼠的肺部组织病理学变化。单独耗竭IL-4显著减轻了细支气管的组织病理学变化，尽管对血管周围的组织病理学变化没有影响。单独耗竭IL-10没有效果。耗竭IFN-γ、IL-2或两者一起对观察到的组织病理学变化没有影响。这些数据表明，FI-RSV免疫引发了对随后RSV感染的Th2、IL-4和IL-10依赖性炎症反应。这一过程可能在接种FI-RSV的婴幼儿中观察到的疾病加重中起了作用。
