Gavett S H, O'Hearn D J, Li X, Huang S K, Finkelman F D, Wills-Karp M
Department of Environmental Health Sciences, Johns Hopkins University, Baltimore, Maryland 21205, USA.
J Exp Med. 1995 Nov 1;182(5):1527-36. doi: 10.1084/jem.182.5.1527.
Allergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a murine model that antigen-induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4+ T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mRNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration of IL-12 (1 microgram/d x 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) gamma and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-gamma, because concurrent treatment with IL-12 and anti-IFN-gamma monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.
过敏性哮喘的特征为气道高反应性和肺部嗜酸性粒细胞增多，可能由表达Th2细胞因子模式的辅助性T（Th）淋巴细胞介导。白细胞介素（IL）-12可抑制Th2细胞因子的表达及其相关反应，包括嗜酸性粒细胞增多、血清免疫球蛋白E和黏膜肥大细胞增多。我们之前在小鼠模型中表明，抗原诱导的气道高反应性和肺部嗜酸性粒细胞增多是CD4 + T细胞依赖性的。我们利用该模型确定IL-12预防抗原诱导的气道高反应性增加、支气管肺泡灌洗（BAL）嗜酸性粒细胞增多以及肺Th2细胞因子表达的能力。致敏的A/J小鼠在单次或重复经气管给予绵羊红细胞抗原刺激后，出现气道高反应性，BAL嗜酸性粒细胞及其他炎症细胞数量增加。抗原刺激后，肺中Th2细胞因子IL-4和IL-5的mRNA和蛋白水平升高。在单次抗原刺激时给予IL-12（1微克/天×5天）可消除气道高反应性和肺部嗜酸性粒细胞增多，并促进干扰素（IFN）-γ增加，IL-4和IL-5表达减少。IL-12的作用部分依赖于IFN-γ，因为IL-12与抗IFN-γ单克隆抗体同时处理可部分逆转IL-12对气道高反应性和嗜酸性粒细胞增多的抑制作用。在第二次抗原刺激时用IL-12处理小鼠也可预防气道高反应性，并显著减少BAL炎症细胞数量，这反映了IL-12抑制与持续抗原诱导的肺部炎症相关反应的能力。这些数据表明，抗原诱导的气道高反应性和炎症可被抑制Th2细胞因子表达的IL-12阻断。局部给予IL-12可能为治疗诸如特应性哮喘等肺部过敏性疾病提供一种新的免疫疗法。
