Immune Tolerance and Immune Deviation Protect Against A*

描述(由申请人提供)： 这个项目的长期目标是了解人类免疫生物学。 哮喘和过敏性疾病。虽然我们对Th2的作用的了解 在过去的10年里，哮喘发病机制的反应有所改善， 我们对抑制Th2偏向炎症和 预防哮喘的作用仍然是最基本的。Th1细胞 可能在预防哮喘方面有作用，然而，我们最近的研究 表明多个附加机制在以下方面发挥更关键作用 调节哮喘和过敏症。在这份提案中，我们将确定和审查 详细地讲，这些下调Th2反应的额外免疫机制， 并确定参与保护的细胞类型和分子 对抗Th2偏向的炎症和哮喘。在具体目标1(假设1)中， 我们将确定免疫耐受保护的机制 治疗哮喘和过敏性疾病。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 由呼吸道接触变应原所致，并测定 这些肺树突状细胞诱导的调节细胞特性 细胞。在特定目标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、转化生长因子-CD8细胞和Toll样细胞 受体信号，调节哮喘和过敏性疾病。这些分子， 佐剂热免疫可激活细胞因子和细胞类型 杀死单核细胞增多性李斯特菌(HKL)，一种非常有效的先天刺激因子 免疫系统。我们将研究免疫反应的特点 HKL诱导，有效地下调气道炎症并保护 对抗呼吸道高反应性的发展。最后，在具体目标3 (假设3)我们将确定参与保护病毒的新途径 哮喘，通过研究一种独特的同源BALB/c小鼠品系(HBA)，它能产生 低水平的IL-4，并抑制呼吸道高反应性的发展。在……里面 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 利用基因芯片比较特定基因和分子 在BALB/c和HBA小鼠中的通路，从而开发出一种独特的分子 保护性免疫的生物学肖像。这些研究将极大地 扩展我们对预防哮喘的免疫反应的知识 Th2偏向免疫反应，是哮喘和过敏的病理性反应。这些 因此，研究很可能导致极大地改进治疗方法， 预防并有可能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.