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

过敏性气道炎症治疗性 T 细胞的异质性和分子特征。

基本信息

批准号：
10066089
负责人：
Weishan Huang
金额：
$ 37.51万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-16 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066089
关键词：
Affect Age Allergens Allergic Allergic inflammation Antigens Antiinflammatory Effect Biochemical Genetics CD8-Positive T-Lymphocytes CD8B1 gene Cells Chemical Interference Chronic Chronic Disease Collaborations Critical Pathways Data Developed Countries Developing Countries Development Disease Disease model Economic Burden Engineering Environment Exhibits Extrinsic asthma FOXP3 gene Gene Expression Profile Genetic Genetic Engineering Genetic Polymorphism Genomic approach Healthcare Systems Heterogeneity Human IL10 gene Immune Immunotherapy In Vitro Individual Inflammation Inflammatory Inflammatory Response Interleukin-10 Knowledge Lung Lung Inflammation Lymphocyte Maintenance Mediator of activation protein Methods Molecular Molecular Profiling Mus Pathogenicity Pathway interactions Patients Physiological Population Prevalence Preventive therapy Production Protocols documentation Receptor Signaling Regulatory T-Lymphocyte Risk Role Severities Signal Pathway Specificity Surface T cell differentiation T cell response T-Cell Development T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Therapeutic Effect Transgenic Mice United States Work airway hyperresponsiveness airway inflammation allergic airway inflammation asthmatic airway base chemical genetics cytokine disorder control effective therapy effector T cell experimental study genetic approach immunoregulation in vitro Assay in vivo innovation interleukin-10 receptor molecular marker mouse model novel response success therapeutic biomarker transcription factor transcriptomics translational study urban area

项目摘要

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.

项目概要/摘要过敏性气道炎症影响全球约 3.34 亿人，其中 13.6% 的人口，其比率在城市化国家和发展中国家都在持续增加。这种疾病影响所有年龄段的患者，通常会发展为慢性疾病。没有治愈方法过敏性哮喘，使其成为发达国家医疗保健系统最昂贵的疾病之一国家。这使得我们的工作非常重要。过敏性气道炎症的特点是炎症细胞因子水平升高，例如 Th2 和 Th17 细胞产生的炎症细胞因子，这些细胞因子具有反作用受具有抑制功能的免疫细胞调节。白介素 10 (IL-10) 是一种免疫调节细胞因子具有已证实的抗炎作用。遗传缺陷或多态性导致缺失或 IL-10 产生的减少与过敏性炎症风险增加相关。两者都有致病性 Th2和Th17可表达高水平的IL-10受体，IL-10直接作用于Th2和Th17以限制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疗法是过敏原特异性免疫疗法（过敏原-SIT）。过敏原 SIT 的成功与 IL- 的诱导相关 10 产生 T 细胞。我们发现，在各种肺部炎症模型中，T细胞是 IL-10 产生的主要贡献者，主要由三个产生 IL-10 的 T 细胞亚群组成： CD4+ Foxp3+ 调节性 T (Treg)、CD4+ Foxp3- IL-10hi 1 型调节性 T (Tr1) 和 CD8+ IL-10+ T 细胞。我们诱导和在体外扩增产生 IL-10 的 T 细胞，并发现这些细胞对小鼠具有深远的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 细胞目前被称为 Tr1 细胞特征的异质分子标记缺乏区分 IL- 10 产生 T 细胞亚群。基于这些发现，我们假设分子特征和与产生 IL-10 的治疗性 T 细胞的异质性相关的途径可用于识别和分离治疗性 T 细胞，并可对其进行操作以促进发育和这些细胞对过敏性哮喘的治疗作用。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-之间和内部的异质性产生T细胞亚群； c) 这些细胞的分子特征和可用于操纵过敏性哮喘治疗性 T 细胞的发育和功能。这部作品的水准很高创新，因为我们利用综合生化、遗传学和基因组学方法，具有独特的转基因小鼠模型，并拥有令人兴奋的初步数据，可以扩展以提供信息集更好地了解肺部炎症疾病的控制，并帮助制定策略操纵产生 IL10 的 T 细胞的发育和功能作为抗过敏的潜在疗法气道炎症和其他相关炎症性疾病。