Regulatory T Cell Inhibition of Natural Killer Cells in COPD

摘要 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，这对退伍军人的影响不成比例。需要新的治疗方法， 目前的治疗和戒烟都不能阻止肺功能一旦开始就不可逆转的下降。的 炎性细胞的慢性浸润是COPD的标志，并且是先天性和适应性的结果 免疫反应。自然杀伤细胞（NK）是一种先天性细胞，已被证明可介导快速免疫应答。 在COPD中对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细胞对肺实质的细胞毒性， 危及免疫监视为此，已显示调节性T细胞（TCFs）抑制NK 但已知COPD患者的TcR会降低，这表明TcR的丢失可能导致COPD患者的TcR降低。 COPD中肺NK细胞毒性增加。我们的中心假设是，增加Treg功能将 阻断来自COPD患者的肺NK的细胞毒性，并将减少小鼠中NK驱动的肺破坏。 COPD模型我们的建议将使用人类肺组织和配对的外周血， 香烟烟雾暴露的小鼠模型。目的1将证实循环人THBVDNA的能力， 在体外抑制肺NK细胞毒性，并将确定这是否限于特定的Treg亚群。后 为了证实TdR调节NK的潜力，我们将专注于解决关键的知识缺口 这对于设计COPD新型Treg疗法的试验至关重要。目标2的目标是测试体内 将Treg亚群过继转移到我们的鼠模型中的效果。具体来说，我们将评估Treg NK和T细胞的抑制，也决定了炎症环境如何影响Treg表型， 稳定和移民。在目标3中，我们将专注于提高TdR的稳定性，因为它们已被证明 当被引入促炎环境时具有功能可塑性。提高了系统的稳定性， 此外，它还可以增加长期的抑制潜力。最后，我们将测试我们的 在6个月的香烟烟雾暴露小鼠模型中优化Treg治疗，并确定我们是否可以 阻止肺部的进一步破坏该项目的成功完成将提供关键数据，这些数据不是 目前可用的关于Treg疗法调节NK细胞毒性和治疗COPD的潜力。有 目前有>280项正在进行的使用Treg疗法治疗自身免疫性疾病和器官移植的临床试验。 移植，但没有研究的Treg治疗COPD。

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.