Immune Tolerance/Immune Deviation Protect Against Asthma

描述（由申请人提供）： 该项目的长期目标是了解 哮喘和过敏性疾病。虽然我们对Th 2的作用的了解 哮喘发病机制的反应在过去10年中有所改善， 我们对抑制Th 2偏向性炎症的机制的理解， 防止哮喘发展的机制还很不成熟th 1细胞 可能在预防哮喘中起作用，然而，我们最近的研究 表明多个额外机制在以下方面发挥更重要作用： 调节哮喘和过敏。在本提案中，我们将确定并审查 详细描述这些下调Th 2应答的额外免疫机制， 并确定参与保护的细胞类型和分子 对抗Th 2型炎症和哮喘。在具体目标1（假设1）中， 我们将确定免疫耐受保护 对抗哮喘和过敏性疾病。我们将定义细胞和 肺树突状细胞介导T细胞耐受的分子事件 通过呼吸道暴露于过敏原诱导，并确定 这些肺树突状细胞诱导的调节细胞的特性 细胞在具体目标2（假设2）中，我们将通过以下方式确定机制： 其中免疫偏离，涉及IL-10、TGF-β CD 8细胞和Toll样 受体信号传导，调节哮喘和过敏性疾病。这些分子 细胞因子和细胞类型通过用佐剂热进行免疫来激活 杀死单核细胞增生李斯特菌（HKL），一种非常有效的先天性 免疫系统我们将研究免疫反应的特征 HKL诱导，其有效下调气道炎症并保护 防止气道高反应性的发展。第三，具体目标 （假设3）我们将确定新的途径参与保护， 哮喘，通过研究一种独特的同类BALB/c小鼠品系（HBA）， 低水平的IL-4和抵抗气道高反应性的发展。在 与斯坦福大学的帕特里克布朗博士合作，我们将利用基因表达 用cDNA微阵列分析来比较特定基因和分子 在BALB/c和HBA小鼠中， 保护性免疫的生物学写照。这些研究将大大 扩展我们对预防哮喘的免疫反应的知识， 哮喘和过敏的病理性th 2免疫反应。这些 因此，研究可能会大大改善治疗方法， 预防和潜在地治愈哮喘和过敏性疾病。

DESCRIPTION (provided by applicant): The long-term goals of this project are to understand the immunobiology of asthma and allergic diseases. While our knowledge of the role of Th2 responses in the pathogenesis of asthma has improved over the past 10 years, our understanding of the mechanisms that dampen Th2 biased inflammation and that protect against the development of asthma remains rudimentary. Th1 cells may have a role in protection against asthma, however, our recent studies indicate that multiple additional mechanisms play more critical roles in regulating asthma and allergy. In this proposal we will identify and examine in detail these additional immune mechanisms that down-modulate Th2 responses, and determine the cell types and molecules that participate in the protection against Th2-biased inflammation and asthma. In Specific Aim 1 (Hypothesis 1), we will determine the mechanisms by which immunological tolerance protects against asthma and allergic disease. We will define the cellular and molecular events by which pulmonary dendritic cells mediate T cell tolerance induced by the respiratory exposure to allergen, and determine the characteristics of the regulatory cells induced by these pulmonary dendritic cells. In Specific Aim 2 (Hypothesis 2), we will determine the mechanisms by which immune deviation, involving IL-10, TGF- CD8 cells and toll-like receptor signaling, regulates asthma and allergic disease. These molecules, cytokines and cell types are activated by immunization with the adjuvant heat killed Listeria monocytogenes (HKL), a very effective stimulator of the innate immune system. We will examine the characteristics of immune responses induced with HKL, which potently down regulate airway inflammation and protect against the development of airway hyperreactivity. Finally, in Specific Aim 3 (Hypothesis 3) we will identify novel pathways involved in protection against asthma, by studying a unique congenic BALB/c mouse strain (HBA), that produces low levels of IL-4 and resists the development of airway hyperreactivity. In collaboration with Dr. Patrick Brown at Stanford, we will use gene expression profiling with cDNA microarrays to compare the specific genes and molecular pathways in BALB/c versus HBA mice, thereby developing a distinctive molecular portrait of the biology of protective immunity. These studies will greatly extend our knowledge of immune responses that protect against asthma and the Th2 biased immune responses that are pathologic for asthma and allergy. These studies therefore, are likely to lead to greatly improved therapies that protect against and potentially cure asthma and allergic diseases.