IMMUNOMODULATION OF ALLERGIC AIRWAY INFLAMMATION BY IL1

哮喘是一种常见的呼吸道炎症性疾病。的发病率和 哮喘死亡率持续上升，尽管使用 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，气道嗜酸性粒细胞增多、血清IgE升高和Th 2 细胞因子的产生在过敏性鼻炎的发病机制中起重要作用 气道炎症和支气管高反应性。 先前的研究 报道IL-12促进Th 1细胞因子，但抑制Th 2细胞因子 合成并抑制IgE产生。基于这些特性， 假设IL-12治疗可以抑制过敏性气道 炎症 过敏原诱导的嗜酸性肺小鼠模型 炎症被开发来测试这一假设。初步结果 表明IL-12处理小鼠抑制支气管肺泡灌洗 (BAL)过敏原激发后嗜酸性粒细胞增多症减少 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-10的表达。 10（Th 2细胞因子）mRNA。的 该提案的总体目标是进一步确定IL的影响， 12在相同的小鼠模型中。这将通过测试 以下假设：（1）IL-12治疗减少了在小鼠中的细胞数量。 嗜酸性粒细胞和嗜酸性粒细胞脱粒的程度在BAL液 以及气道粘膜和粘膜下层。(2)IL-12治疗降低 气管环对乙酰胆碱的反应性。(3)IL-12治疗改变 通过下调Th 2，在BAL T辅助细胞中细胞因子mRNA表达 细胞因子和上调Th 1细胞因子。(4)IL-12治疗降低 产生Th 2细胞因子的CD 4 + T细胞的数量，但增加 肺中产生Th 1细胞因子的数量。 这些研究可能会使 评估IL-12作为治疗剂未来临床研究的阶段 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.