The Role of IL-10 in Regulation of Allergic Inflammation

持续性嗜酸性炎症是哮喘的主要特征，具有重要的生理后果。过敏性炎症反应的强度不能区分过敏性受试者是否患有哮喘。然而，哮喘的炎症会持续很长时间。因此，关闭炎症的信号在促进过敏性炎症的消退中可能是至关重要的。一个假定的关闭因子是细胞因子白介素10[IL-10]，它诱导嗜酸性粒细胞凋亡，并抑制肿瘤坏死因子-1的产生。我们已经证明，过敏性哮喘患者的肺组织中几乎没有IL-10的表达，相比之下，过敏性非哮喘患者的IL-10水平比健康志愿者高。我们提出以下中心假说：IL-10对过敏性炎症的消退至关重要。一种基因工程的IL-10缺陷“敲除”(IL-10i)小鼠品系提供了对IL-10在过敏性炎症过程中的作用进行关键的机械测试的机会。因此，具体目的是建立：1)过敏原致敏和激发后炎症和生理变化的发生和消退的模式和时机，以及过敏致敏的程度和特征；2)AIM 1观察的基础机制；3)IL-10在介导过敏原激发后的抗炎反应中的特异性；以及4)肿瘤坏死因子-“在使过敏原激发的炎症反应中的作用。这些细胞因子与人类哮喘有直接和明显的相关性。IL-10i小鼠和对照品系动物将经历变应原敏化和挑战；变应原特异性IgE、Th1-Th2淋巴细胞的分化、变应原驱动的炎症和呼吸道高反应性将是关键的结果变量。此外，功能敲除动物将通过注射中和IL-10抗体产生，并将进行类似的研究。这些信息将为IL-10在调节过敏性炎症中的作用提供直接证据，并将有助于确定炎症和呼吸道高反应性之间的关系。

Persistent eosinophilic inflammation is a principal characteristic of asthma, with important physiologic consequences. The intensity of the allergic inflammatory response does not differentiate allergic subjects, with and without asthma. Inflammation in asthma, however, is prolonged. Therefore, signals that switch-off inflammation may be crucial in promoting resolution of allergic inflammation. One putative switch-off factor is the cytokine interleukin-10 [IL-10], which induces eosinophil apoptosis, and suppresses TNF-" production. We have shown that lung expression of IL-10 in allergic asthmatics is virtually absent, in contrast to allergic non- asthmatics, in whom IL-10 levels are increased compared to healthy volunteers. We propose the following Central Hypothesis: IL-10 is a critically important to the resolution of allergic inflammation. A genetically-engineered IL-10 deficient "knockout" (IL-10i) mouse strain offers the opportunity to perform critical mechanistic tests of the role of IL-10 in the allergic inflammatory process. Accordingly, the Specific Aims are to establish: 1) the pattern and timing of development and resolution of inflammation and physiologic changes following allergen sensitization and challenge, and the degree and characteristics of allergic sensitization; 2) the mechanisms which underlie the observations of Aim 1; 3) the specificity of IL-10 in mediating the anti-inflammatory response after allergen challenge, and 4) the role of TNF-" in enabling the inflammatory response to allergen challenge. These cytokines have direct and demonstrable relevance to human asthma. IL-10i mice and control strain animals will undergo allergen sensitization and challenge; allergen specific IgE, differentiation of Th1-Th2 lymphocytes, allergen-driven inflammation, and airway hyperresponsiveness will be key outcome variables. In addition, functional knock-out animals will be produced by administration of neutralizing IL-10 antibody, and will undergo similar studies. This information will provide direct evidence of the role of IL-10 in regulating allergic inflammation, and will help to ascertain the relationships between inflammation and airway hyperresponsiveness.