Defining the Role of Regulatory T Cells in Resolution of Acute Lung Injury

定义调节性 T 细胞在解决急性肺损伤中的作用

• 批准号: 10316245
• 负责人: Jason Robert Mock
• 金额: $ 58.91万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10316245
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adoptive Transfer; Autoantigens; Autoimmunity; Cell Cycle Kinetics; Cell Proliferation; Cells; Coculture Techniques; Code; Complement; Disease; Epithelial; Epithelial Cells; Experimental Models; FOXP3 gene; Fibrin; Gene Expression; Genes; Genetic Transcription; Histone Deacetylase; Histones; Homing; Immune; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Injury; Knowledge; Light; Liquid substance; Lung; Lung diseases; Lysine; MME gene; Mediating; Morbidity - disease rate; Mus; Patients; Peripheral; Phase; Play; Pneumonia; Process; Protein-Serine-Threonine Kinases; Proteolysis; Publishing; Recovery; Regulatory T-Lymphocyte; Resolution; Role; Sentinel; Severities; Signal Transduction; Streptococcus pneumoniae; Structure of parenchyma of lung; T-Lymphocyte; Technology; Testing; Thymus Gland; Tissues; Transcript; Tumor-infiltrating immune cells; Type II Epithelial Receptor Cell; Untranslated RNA; adaptive immunity; alveolar epithelium; cytokine; improved; improved outcome; in vitro testing; lung injury; lung repair; mortality; novel; pathogen; repaired; reparative process; response; response to injury; therapeutic development; therapy outcome; transcriptome; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adoptive Transfer; Autoantigens; Autoimmunity; Cell Cycle Kinetics; Cell Proliferation; Cells; Coculture Techniques; Code; Complement; Disease; Epithelial; Epithelial Cells; Experimental Models; FOXP3 gene; Fibrin; Gene Expression; Genes; Genetic Transcription; Histone Deacetylase; Histones; Homing; Immune; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Injury; Knowledge; Light; Liquid substance; Lung; Lung diseases; Lysine; MME gene; Mediating; Morbidity - disease rate; Mus; Patients; Peripheral; Phase; Play; Pneumonia; Process; Protein-Serine-Threonine Kinases; Proteolysis; Publishing; Recovery; Regulatory T-Lymphocyte; Resolution; Role; Sentinel; Severities; Signal Transduction; Streptococcus pneumoniae; Structure of parenchyma of lung; T-Lymphocyte; Technology; Testing; Thymus Gland; Tissues; Transcript; Tumor-infiltrating immune cells; Type II Epithelial Receptor Cell; Untranslated RNA; adaptive immunity; alveolar epithelium; cytokine; improved; improved outcome; in vitro testing; lung injury; lung repair; mortality; novel; pathogen; repaired; reparative process; response; response to injury; therapeutic development; therapy outcome; transcriptome

Project Summary There is a paucity of information known about how the lung recovers from acute respiratory distress syndrome (ARDS) and pneumonia, and this knowledge gap has contributed to the continued high morbidity and mortality of these diseases. A subset of immune cells, Foxp3+ regulatory T lymphocytes (Tregs), is thought to be important in resolution in several experimental models of acute lung injury (ALI). Furthermore, Tregs are present in the lung of patients with ARDS, suggesting that they contribute to ARDS recovery. Tregs can arise from either thymic or extra-thymic origins. Extra-thymic, peripherally-induced Tregs (iTregs) are converted from naïve T cells and serve distinct and essential functions in controlling adaptive immunity to restrain immune cell infiltrates in the bronchial and bronchiolar walls. Furthermore, our published studies show that during the resolving phase of lung injury, Tregs expand in number and change their gene expression profiles compared to Tregs in uninjured control lungs. Treg transcriptome profiling identifies several genes that shine a light on novel functions of Tregs during ALI resolution. One transcript that is markedly upregulated 23-fold in Tregs isolated from resolving lung tissue is matrix metalloproteinase 12 (Mmp12). Importantly, mice lacking endogenous Tregs and repleted with Mmp12-/- Tregs by adoptive transfer have elevated inflammatory cells and less epithelial proliferation during resolution than mice repleted with Mmp12+/+ Tregs. The Treg transcriptome also suggests that downregulated expression of Treg transcripts Kdm6b and Sik1, both of which act to regulate gene transcription, may function to regulate Treg homing, retention, stability, and survival. The Aims seek to test the central hypothesis that Tregs are critical to resolution and that by optimizing Treg responses, ALI severity can be reduced, and resolution hastened. Aim 1 investigates the role of iTregs during resolution of ALI resolution. The hypothesis is that iTregs are required for optimal resolution of inflammation and lung repair after ALI induced by LPS, S. pneumoniae, and influenza A. The direct effects of Tregs and iTregs will be determined using in vitro co-cultures of Tregs and AT2 cells. Aim 2 determines the impact of Treg-expressed MMP12 during the resolution of ALI. The hypothesis is that Treg expression of MMP12 exerts multiple roles in orchestrating and facilitating the resolution of ALI. Substrates of Treg MMP12 will be identified in BAL fluid and lung tissue. Aim 3 determines if the differentially regulated transcripts, Kdm6b and Sik1, regulate Treg-promoted resolution of ALI. We will test the hypothesis that Tregs deficient in Kdm6b have decreased Foxp3 expression levels and delayed, inadequate resolution and that Tregs deficient in Sik1 have improved quality of resolution. We anticipate that the proposed studies will determine the roles iTregs play in ALI resolution and identify mechanisms by which Tregs mediate resolution and repair. Identifying and elucidating these mechanisms will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the beneficial response to injury.

项目摘要 关于肺如何从急性呼吸窘迫综合征中恢复的信息很少 （ARDS）和肺炎，这种知识差距导致了持续的高发病率和死亡率 这些疾病。免疫细胞的一部分，Foxp3+调节性T淋巴细胞（Treg）被认为很重要 在几种急性肺损伤（ALI）实验模型中的分辨率中。此外，Tregs存在于 ARDS患者的肺肺有助于ARDS恢复。 treg可以是由任何一种胸腺引起的 或外室外起源。外周外诱导的Treg（ITREGS）从幼稚的T细胞中转化，并 在控制适应性免疫组织化学方面发挥独特而重要的功能，以抑制免疫组织化学细胞浸润 支气管和支气管墙。此外，我们发表的研究表明，在肺的解决阶段 与未受伤的对照中的Treg相比，Treg的数量扩大并改变其基因表达曲线 肺。 Treg转录组分析标识了几个基因，这些基因在Tregs的新功能上发光 阿里解决方案。一个从分离的肺组织分离的Treg中明显更新23倍的成绩单是 基质金属蛋白酶12（MMP12）。重要的是，缺乏内源性Treg并用MMP12 - / - 取代的小鼠 通过自适应转移的Tregs具有升高的炎症细胞，分辨率期间的上皮增殖较少 比用MMP12+/+ Tregs代替的小鼠。 Treg转录组还表明表达式下调 Treg转录本KDM6B和SIK1（两者都可以调节基因转录）可能起作用以调节 Treg Housing，保留，稳定和生存。目的试图检验treg是至关重要的中心假设 为了解决，通过优化Treg响应，可以减少ALI严重性，并加速解决。目的 1研究ITREG在分辨ALI解决方案中的作用。假设是ITREGS是必需的 LPS，肺炎链球菌和影响力A的ALI后，炎症和肺修复的最佳分辨率。 Treg和Itregs的直接影响将使用Treg和AT2细胞的体外共培养确定。目的 2确定在ALI分辨率期间Treg表达的MMP12的影响。假设是Treg MMP12的表达在编排和支持ALI分辨率方面发挥了多种作用。底物 Treg MMP12将在BAL液和肺组织中鉴定。 AIM 3确定是否受到差异调节 转录本KDM6B和SIK1调节ALI的Treg促进分辨率。我们将测试Tregs的假设 KDM6B缺乏提高了FOXP3表达水平，并且延迟，分辨率不足和Tregs 缺乏SIK1的分辨率提高了。我们预计拟议的研究将确定 ITREGS在ALI分辨率中发挥作用，并确定Tregs介导分辨率和修复的机制。 识别和阐明这些机制将允许发展理论方法以最小化 侧支组织损害而不会不利地改变对伤害的有益反应。