Regulatory T Cell Inhibition of Natural Killer Cells in COPD

COPD 中自然杀伤细胞的调节性 T 细胞抑制

• 批准号: 10426277
• 负责人: Christine M. Basmajian
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10426277
• 关键词: Address; Adoptive Transfer; Affect; Animal Model; Apoptosis; Apoptotic; Area; Autoimmune Diseases; Autologous; Automobile Driving; Back; Biological Assay; Biological Process; Blood specimen; CASP3 gene; Cell Death; Cell physiology; Cells; Chronic Inflammatory Infiltrate; Chronic Obstructive Pulmonary Disease; Clinical Trials; Coculture Techniques; Data; Development; Disease; Disease Progression; Environment; Epithelial Cells; FOXP3 gene; Gene Expression Profile; Genes; Goals; Human; Immunity; Immunologic Surveillance; Immunotherapy; In Vitro; Inflammation; Innate Immune Response; Knockout Mice; Knowledge; Link; Lung; Measures; Mediating; Memory; Modeling; Morbidity - disease rate; Mus; NCAM1 gene; Natural Killer Cell toxicity; Natural Killer Cells; Organ Transplantation; Pathogenesis; Pathology; Patients; Phenotype; Population; Proteins; Protocols documentation; Publishing; Pulmonary Emphysema; Regulation; Regulatory T-Lymphocyte; Role; SIRT1 gene; Sampling; Smoker; Smoking; Stains; Structure of parenchyma of lung; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Translations; Veterans; adaptive immune response; airway obstruction; cell type; cigarette smoke; cytotoxic; cytotoxicity; exposure to cigarette smoke; functional plasticity; functional restoration; improved; in vivo; in vivo evaluation; inflammatory milieu; inhibitor; lung injury; mRNA Expression; migration; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; peripheral blood; pre-clinical; prevent; pulmonary function; smoking cessation; targeted treatment; therapeutically effective; trial design; tumor

ABSTRACT Chronic obstructive pulmonary disease (COPD) is a highly prevalent disorder that is primarily attributed to smoking, and which disproportionately affects Veterans. New therapeutic approaches are needed as neither current therapies nor smoking cessation halt the irreversible decline in lung function once initiated. The chronic infiltration of inflammatory cells is a hallmark of COPD and results from both innate and adaptive immune responses. Natural killer cells (NKs) are innate cells that have been shown to mediate rapid cytotoxicity towards autologous lung epithelial cells in COPD. Our long-term goal is to understand whether we can use an immunotherapy approach to suppress lung NK cytotoxicity against lung parenchyma without compromising immune surveillance. To this end, regulatory T cells (Tregs) have been shown to suppress NKs but Tregs are known to be decreased in COPD, suggesting that the loss of Tregs may be contributing to the increased cytotoxicity of lung NKs in COPD. Our Central Hypothesis is that increasing Treg functionality will block the cytotoxicity of lung NKs from COPD patients and will reduce NK-driven lung destruction in a murine model of COPD. Our proposal will use human lung tissue and paired peripheral blood and an established murine model of cigarette smoke exposure. Aim 1 will confirm the ability of circulating human Tregs to suppress lung NK cytotoxicity in vitro and will determine whether this is limited to a specific Treg subset. After confirming the potential for Tregs to modulate NKs, we will focus on addressing critical knowledge gaps essential to designing trials of novel Treg therapies in COPD. The goal of Aim 2 will be to test the in vivo effects of adoptively transferring Treg subsets into our murine model. Specifically, we will evaluate Treg suppression of NKs and T cells and also determine how the inflammatory environment effects Treg phenotype, stability, and migration. In Aim 3, we will focus on improving the stability of Tregs as they have been shown to have functional plasticity when introduced to a proinflammatory environment. Increasing the stability of the Tregs should also increase their long-term suppressive potential. We will conclude by testing the effects of our optimized Treg therapy in a 6-month cigarette smoke exposure murine model and determine whether we can halt progressive lung destruction. Successful completion of this project will provide crucial data, which are not currently available, on the potential of Treg therapy to regulate NK cytotoxicity and treat COPD. There are currently >280 ongoing clinical trials using Treg therapy for the treatment of autoimmune disease and organ transplant, but there are no studies of Treg therapy in COPD.

抽象的 慢性阻塞性肺疾病 (COPD) 是一种高度流行的疾病，主要归因于 吸烟，这对退伍军人影响尤为严重。需要新的治疗方法，因为两者都不是 目前的治疗或戒烟一旦开始就无法阻止肺功能的不可逆转的下降。这 炎症细胞的慢性浸润是 COPD 的标志，是先天性和适应性的结果 免疫反应。自然杀伤细胞 (NK) 是先天细胞，已被证明能够介导快速介导 对 COPD 中自体肺上皮细胞的细胞毒性。我们的长期目标是了解我们是否 可以使用免疫治疗方法来抑制肺 NK 对肺实质的细胞毒性，而无需 损害免疫监视。为此，调节性 T 细胞 (Treg) 已被证明可以抑制 NK 但已知在慢性阻塞性肺病 (COPD) 中 Tregs 会减少，这表明 Tregs 的缺失可能会导致 COPD 中肺 NK 的细胞毒性增加。我们的中心假设是增加 Treg 功能将 阻断 COPD 患者肺部 NK 的细胞毒性，并减少小鼠体内 NK 驱动的肺部破坏 慢性阻塞性肺病模型。我们的建议将使用人类肺组织和配对的外周血以及已建立的 香烟烟雾暴露的小鼠模型。目标 1 将确认循环人类 Tregs 的能力 体外抑制肺 NK 细胞毒性，并将确定这是否仅限于特定的 Treg 亚群。后 确认 Tregs 调节 NK 的潜力后，我们将重点解决关键的知识差距 对于设计 COPD 新型 Treg 疗法的试验至关重要。 Aim 2 的目标是测试体内 将 Treg 子集过继转移到我们的小鼠模型中的效果。具体来说，我们将评估Treg 抑制 NK 和 T 细胞，并确定炎症环境如何影响 Treg 表型， 稳定性和迁移。在目标 3 中，我们将专注于提高 Tregs 的稳定性，因为它们已被证明可以 当引入促炎环境时具有功能可塑性。增加稳定性 Tregs 还应该增加其长期抑制潜力。我们将通过测试我们的效果来得出结论 在 6 个月香烟烟雾暴露小鼠模型中优化 Treg 疗法，并确定我们是否可以 停止进行性肺部破坏。该项目的成功完成将提供关键数据，而这些数据不是 目前，Treg 疗法在调节 NK 细胞毒性和治疗 COPD 方面的潜力。有 目前超过 280 项正在进行的使用 Treg 疗法治疗自身免疫性疾病和器官的临床试验 移植，但尚无针对 COPD 的 Treg 治疗的研究。