Heterogeneity and molecular signatures of therapeutic T cells in allergic airwayinflammation.

项目概要/摘要 过敏性气道炎症影响全球约3.34亿人，其中包括13.6%的 美国的人口，其比率继续增加，在城市化和发展中国家。 这种疾病折磨所有年龄段的患者，通常进展为慢性疾病。无法治愈 过敏性哮喘，使其成为发达国家医疗保健系统最昂贵的疾病之一， 国家这使我们的工作非常重要。过敏性气道炎症的特征是 升高的炎性细胞因子水平，例如由Th 2和Th 17细胞产生的那些，其是反- 由具有抑制功能的免疫细胞调节。白细胞介素-10（IL-10）是一种免疫调节细胞因子 具有抗炎作用。遗传缺陷或多态性导致缺乏或 IL-10产生的减少与变应性炎症的风险增加有关。致病的 Th 2和Th 17可以表达高水平的IL-10受体，并且IL-10直接作用于Th 2和Th 17以限制IL-10的表达。 它们在炎症过程中的发育和功能。迄今为止，过敏性哮喘的唯一预防性治疗是 过敏原特异性免疫疗法（allergen-SIT）变应原-SIT的成功与IL-10的诱导相关。 10-产生T细胞。我们已经发现，在各种肺部炎症疾病模型中，T细胞是 IL-10产生的主要贡献者，主要由三种产生IL-10的T细胞亚群组成：CD 4 + Foxp 3 + 调节性T（Treg）、CD 4 + Foxp 3- IL-10 hi 1型调节性T（Tr 1）和CD 8 + IL-10+ T细胞。我们诱导， 在体外扩增了产生IL-10的T细胞，并在小鼠中发现了这些细胞的深远治疗作用。 过敏性气道炎症模型。进一步的实验表明，这些产生IL-10的T细胞是 目前称为Tr 1细胞标记的分子标记缺乏区分IL-10的能力。 10-产生T细胞亚群。基于这些发现，我们假设分子特征和 可以利用与产生IL-10的治疗性T细胞的异质性相关的途径， 鉴定和分离治疗性T细胞，并且可以被操纵以促进其发育， 这些细胞在过敏性哮喘中的治疗作用。我们提出了三个具体目标的实验， 确定：a）治疗性T细胞的有效成分; B）IL-10- 1之间和内部的异质性。 产生T细胞亚群;和c）这些细胞的分子特征和可用于 操纵过敏性哮喘中治疗性T细胞的发育和功能。这项工作是高度 创新，因为我们利用全面的生物化学，遗传和基因组学方法， 转基因小鼠模型，并有令人兴奋的初步数据，可以扩大提供信息集 为了更好地了解肺炎性疾病的控制，以及帮助制定战略， 操纵产生IL 10的T细胞的发育和功能作为抗过敏性疾病的潜在疗法 气道炎症和其它相关的炎性疾病。

Project Summary / Abstract Allergic airway inflammation affects approximately 334 million people worldwide, including 13.6% of the population of the United States, and its rate continues to increase in both urbanized and developing countries. This disease afflicts patients of all ages and normally progresses to chronic illness. There is no cure for allergic asthma, making it one of the most expensive diseases for healthcare systems in developed countries. This makes our work highly significant. Allergic airway inflammation is characterized with elevated levels of inflammatory cytokines such as those produced by Th2 and Th17 cells, which are counter- regulated by immune cells with suppressive function. Interleukin-10 (IL-10) is an immunomodulatory cytokine with demonstrated anti-inflammatory effects. Genetic deficiency or polymorphisms resulting in the absence or reduction of IL-10 production are associated with increased risk of allergic inflammation. Both the pathogenic Th2 and Th17 can express high levels of IL-10 receptor, and IL-10 directly functions on Th2 and Th17 to limit their development and function during inflammation. To date, the only preventive therapy for allergic asthma is allergen-specific immunotherapy (allergen-SIT). The success of allergen-SIT correlates with the induction of IL- 10-producing T cells. We have found that, in various pulmonary inflammatory disease models, T cells are the major contributors to IL-10 production, mainly composed of three IL-10-producing T cell subsets: CD4+ Foxp3+ regulatory T (Treg), CD4+ Foxp3- IL-10hi type 1 regulatory T (Tr1) and CD8+ IL-10+ T cells. We induced and expanded the IL-10-producing T cells in vitro and found a profound therapeutic effect of these cells in a murine model of allergic airway inflammation. Further experiments revealed that these IL-10-producing T cells are heterogeneous, and molecular markers currently known as Tr1 cell signatures lack the ability to distinguish IL- 10-producing T cell subsets. Based on these findings, we hypothesize that molecular signatures and pathways associated with the heterogeneity of IL-10-producing therapeutic T cells can be exploited to identify and isolate therapeutic T cells, and can be manipulated to promote the development and therapeutic effect of these cells in allergic asthma. We propose experiments in three Specific Aims to determine: a) the effective components of the therapeutic T cells; b) the heterogeneity among and within IL-10- producing T cell subsets; and c) the molecular signatures of these cells and pathways that can be exploited to manipulate the development and function of therapeutic T cells in allergic asthma. This work is highly innovative as we utilize comprehensive biochemical, genetic and genomics approaches with unique transgenic mouse models, and have exciting preliminary data that can be expanded to provide information sets for a better understanding of pulmonary inflammatory disease control, as well as to help develop strategies to manipulate the development and function of IL10-producing T cells as a potential therapy against allergic airway inflammation and other related inflammatory diseases.