IMMUNOMODULATION OF ALLERGIC AIRWAY INFLAMMATION BY IL1

哮喘是常见的呼吸道炎症性疾病。发病率和 哮喘的死亡率继续上升，尽管使用了 目前可用的治疗剂。这引发了一场激烈的 寻找治疗哮喘和过敏性炎症的新方法。 有证据表明，呼吸道嗜酸性粒细胞增多，血清IgE和Th2升高 细胞因子的产生在变态反应性疾病的发病机制中起重要作用 呼吸道炎症和支气管高反应性。先前的研究已经 报道称，IL-12促进Th1细胞因子，但抑制Th2细胞因子 合成并抑制IgE的产生。基于这些特性，它是 假设IL-12治疗可能抑制过敏性呼吸道 发炎。小鼠变应原诱导的嗜酸性粒细胞增多性肺模型 炎症就是为了验证这一假设而发展起来的。初步结果 IL-12对小鼠肺泡灌洗的抑制作用 (BAL)气管内变应原激发后的嗜酸性粒细胞增多，减少 过敏原特异性血清IgE水平，抑制气管环反应性 乙酰胆碱，并下调IL-4、IL-5和IL-2的表达 10(Th2细胞因子)在未分离的晚期BAL细胞中的表达。这个 这项建议的总体目标是进一步定义IL- 12只在相同的小鼠模型中。这将通过测试 以下假设：(L)IL-12治疗可减少 支气管肺泡灌洗液中嗜酸性粒细胞和嗜酸性粒细胞脱颗粒程度 在呼吸道粘膜和粘膜下层。(2)IL-12治疗减少 气管环对乙酰胆碱的反应性。(3)IL-12治疗改变 BAL辅助性T细胞通过下调Th2表达细胞因子 细胞因子和上调Th1细胞因子。(4)IL-12治疗减少 产生Th2细胞因子的CD4+T细胞的数量，但增加 肺中产生Th1细胞因子的数量。这些研究可能会设定 评估IL-12作为治疗剂的未来临床研究阶段 治疗哮喘。

Asthma is a common inflammatory disease of the airways. The morbidity and mortality from asthma have continued to increase, despite usage of currently available therapeutic agents. This has prompted an intense search for new methods of treating asthma and allergic inflammation. Evidence indicates that airway eosinophilia, elevated serum IgE, and Th2 cytokine production play important roles in the pathogenesis of allergic airway inflammation and bronchial hyperresponsiveness. Prior studies have reported that IL-12 promotes Th1 cytokines, but inhibits Th2 cytokine synthesis and suppresses IgE production. Based on these properties, it was hypothesized that IL-12 treatment may suppress allergic airway inflammation. A mouse model of allergen-induced eosinophilic lung inflammation was developed to test this hypothesis. Preliminary results indicate that IL-12 treatment of mice inhibits bronchoalveolar lavage (BAL) eosinophilia following intratracheal allergen challenge, decreases allergen-specific serum IgE levels, inhibits tracheal ring reactivity to acetylcholine in vitro, and downregulates expression of IL-4, IL-5 and IL- 10 (Th2 cytokines) mRNA in unfractionated late phase BAL cells. The overall objective of this proposal is to further define the effects of IL- 12 in the same murine model. This will be accomplished by testing the following hypothesis: (l) IL-12 treatment decreases the number of eosinophils and the extent of eosinophil degranulation in the BAL fluids and in the airway mucosa and submucosa. (2) IL-12 treatment decreases tracheal ring reactivity to acetylcholine. (3) IL-12 treatment alters cytokines mRNA expression in BAL T-helper cells, by downregulating Th2 cytokines and upregulating Th1 cytokines. (4) IL-12 treatment decreases the number of CD4+ T-cells producing Th2 cytokines, but increases the number producing Th1 cytokines in the lungs. These studies may set the stage for future clinical research evaluating IL-12 as a therapeutic agent for asthma.