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。

• 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
• 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; 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

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.

项目摘要 /摘要 过敏性气道炎症影响了全球约3.34亿人，其中包括13.6％ 在城市化和发展中国家，美国的人口及其比率不断提高。 这种疾病困扰着各个年龄段的患者，通常会发展为慢性病。无法治愈 过敏性哮喘，使其成为发展中医疗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 炎性细胞因子的水平升高，例如Th2和Th17细胞产生的细胞因子，它们是对立的 由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 具有抗炎作用。遗传缺乏或多态性导致缺乏或 IL-10产生的降低与过敏性炎症的风险增加有关。致病性 Th2和Th17可以表达高水平的IL-10受体，而IL-10直接在Th2和Th17上起作用以限制 它们在炎症期间的发育和功能。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）。过敏原-ET的成功与诱导IL-相关 10产生的T细胞。我们发现，在各种肺部炎性疾病模型中，T细胞是 IL-10产生的主要贡献者，主要由三个IL-10产生的T细胞子集组成：CD4+ FOXP3+ 调节性T（TREG），CD4+ FOXP3- IL-10HI 1型调节t（TR1）和CD8+ IL-10+ T细胞。我们诱导了 在体外扩展了IL-10产生的T细胞，发现这些细胞在鼠中具有深远的治疗作用 过敏性气道炎症的模型。进一步的实验表明，这些产生IL-10的T细胞是 异质性和分子标记物当前称为TR1细胞特征缺乏区分IL-的能力 10产生的T细胞子集。基于这些发现，我们假设分子特征和 与IL-10产生治疗性T细胞的异质性相关的途径可以被利用为 识别和隔离治疗性T细胞，可以操纵以促进发展和 这些细胞在过敏性哮喘中的治疗作用。我们提出了三个特定目标的实验 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细胞子集； c）这些细胞和途径的分子特征可以被利用为 操纵过敏性哮喘治疗性T细胞的发育和功能。这项工作很高 当我们利用具有独特的全面生化，遗传和基因组学方法时，创新 转基因鼠标模型，并具有令人兴奋的初步数据，可以扩展以提供信息集 为了更好地了解肺部炎症性疾病的控制，并帮助制定策略 操纵产生IL10的T细胞的发育和功能作为针对过敏性的潜在疗法 气道炎症和其他相关炎症性疾病。