Natural Killer Cell Functions in Lymphangioleiomyomatosis

自然杀伤细胞在淋巴管平滑肌瘤病中的功能

• 批准号: 10323021
• 负责人: Michael Borchers
• 金额: $ 40万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323021
• 关键词: Address; Affect; Animal Model; Antibody Therapy; Autoimmune Diseases; Autopsy; Blood Circulation; Case Study; Cell Proliferation; Cell physiology; Cells; Data; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Estrogens; Event; Exhibits; Future; Goals; Growth; Immunocompetent; Immunologic Surveillance; Impairment; Investigation; Lead; Leiomyoma; Ligands; Lung; Lung diseases; Lung nodule; Lymphangioleiomyomatosis; Lymphocyte; MAP Kinase Gene; Malignant Neoplasms; Mediator of activation protein; Messenger RNA; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Morbidity - disease rate; Mutation; NK Cell Activation; Natural Killer Cells; Neoplasm Metastasis; Nodule; Organ; Organ failure; Pathogenesis; Pathogenicity; Pathologic Processes; Pathway interactions; Patients; Phenotype; Phosphoproteins; Physicians; Population; Process; Progesterone Receptors; Prognostic Marker; Proliferating; Protein Analysis; Public Health; Regulation; Reporting; Research; Role; Sampling; Series; Severity of illness; Shapes; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Stains; Structure of parenchyma of lung; TSC1 gene; TSC2 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Tumor Tissue; Uterus; Woman; advanced disease; base; chronic infection; cytokine; cytotoxic; cytotoxicity; efficacy evaluation; immune function; insight; mortality; mouse model; novel; novel therapeutics; receptor; receptor expression; tumor growth

Project Summary. Lymphangioleiomyomatosis (LAM) is a rare lung disease of women in which abnormally proliferating smooth muscle cells carrying acquired mutations in the TSC1 or TSC2 genes metastasize from an unknown source and infiltrate the lung. The proliferating smooth muscle cells lead to destruction of surrounding lung tissue, cystic remodeling, and organ failure. Unfortunately, physicians typically diagnose LAM after significant disease progression. We reported key findings regarding immune function [specifically, natural killer (NK) cells] at this stage of disease in LAM patients, but there is still an unmet need to further define the role of these cells in advanced disease as well as early stages of disease. Early events can be effectively studied using animal models that best reflect the pathological processes leading to LAM. Our preliminary data examining LAM patients and a mouse model of LAM featuring leiomyoma formation and Tsc2-null nodules in the lungs demonstrate the existence of organ-specific alterations in NK cell function that likely contribute to LAM pathogenesis. Specifically, unique subsets of NK cells exist in circulation and lung tissue that are characterized as “hyperresponsive” in terms of cytotoxicity and cytokine responsiveness. We also examined earlier stages of disease using a mouse model employing a uterine specific Tsc2 deletion which develop hallmark features of LAM including leiomyoma formation and accumulation of pulmonary nodules consisting of smooth muscle cells carrying Tsc2 deletions. We show that the leiomyomas express high levels of ligands for the NKG2D activating receptor but also elaborate high levels of soluble ligands that likely downregulate NKG2D expression and impaired NK cell function. The preliminary data demonstrates a dynamic shaping of NK cell phenotype and function throughout the arc of pathogenesis. The goal of this proposal is to define the phenotype, function, and role of NK cells and NKG2D in LAM using both LAM patient samples and animal models. Towards this goal, we will 1) Define the functional significance of unique NK cell populations in LAM. 2) Define the mechanism of VEGFD-amplified NK cell activation. 3) Define the function of NK cells and Nkg2d in the initiation and progression of LAM. And 4) Define the efficacy and benefits of therapeutic inhibition of circulating soluble Nkg2d ligands. The successful completion of these studies is likely to have a high impact on our understanding of LAM pathogenesis. The role of cytotoxic lymphocytes such as NK cell are clear in terms of the multiple stages of disease such as the control of tumor growth and tissue remodeling. We will identify the role of these cells at multiple stages of disease, identify mechanisms of NK cell responsiveness and breakdown of immune surveillance, and examine the potential for therapeutic intervention targeting soluble NKG2D ligands. Several therapeutics aimed at modulating NK cell function are in development for chronic infections, autoimmune diseases, and cancer. Our hope is that these agents will provide new options for therapy, in addition to existing therapies for LAM, in the near future.

项目摘要。淋巴管平滑肌瘤病 (LAM) 是一种罕见的女性肺部疾病，其中异常 携带 TSC1 或 TSC2 基因获得性突变的增殖平滑肌细胞从 来源不明并渗入肺部。增殖的平滑肌细胞导致破坏 周围肺组织、囊性重塑和器官衰竭。不幸的是，医生通常会诊断 疾病显着进展后的 LAM。我们报告了有关免疫功能的重要发现[具体来说， 自然杀伤（NK）细胞]在 LAM 患者的疾病这一阶段，但仍有未满足的需要进一步 定义这些细胞在晚期疾病以及疾病早期阶段的作用。早期事件可以是 使用最能反映导致 LAM 的病理过程的动物模型进行了有效的研究。我们的 检查 LAM 患者和以平滑肌瘤形成为特征的 LAM 小鼠模型的初步数据 肺部 Tsc2 缺失结节证明 NK 细胞功能存在器官特异性改变， 可能有助于 LAM 发病机制。具体来说，独特的 NK 细胞亚群存在于循环系统和肺中 在细胞毒性和细胞因子反应性方面具有“高反应性”特征的组织。我们 还使用子宫特异性 Tsc2 缺失的小鼠模型检查了疾病的早期阶段 形成 LAM 的标志性特征，包括平滑肌瘤形成和肺部积聚 由携带 Tsc2 缺失的平滑肌细胞组成的结节。我们表明平滑肌瘤表达 高水平的 NKG2D 激活受体配体，而且还精心设计了高水平的可溶性配体 可能下调 NKG2D 表达并损害 NK 细胞功能。初步数据表明 在整个发病机制中动态塑造 NK 细胞表型和功能。此举的目标 提案是使用 LAM 患者来定义 NK 细胞和 NKG2D 在 LAM 中的表型、功能和作用 样品和动物模型。为了实现这一目标，我们将 1) 定义独特 NK 细胞的功能意义 LAM 中的人口。 2) 定义VEGFD扩增的NK细胞激活机制。 3）定义函数 NK 细胞和 Nkg2d 在 LAM 的启动和进展中的作用。 4) 定义功效和益处 循环可溶性 Nkg2d 配体的治疗性抑制。这些研究的成功完成是有可能的 对我们对 LAM 发病机制的理解产生重大影响。细胞毒性淋巴细胞的作用，例如 NK细胞在疾病的多个阶段如控制肿瘤生长和组织方面具有明确的作用 重塑。我们将确定这些细胞在疾病多个阶段的作用，确定 NK 的机制 细胞反应和免疫监视的崩溃，并检查治疗的潜力 针对可溶性 NKG2D 配体的干预。几种旨在调节 NK 细胞功能的疗法是 正在针对慢性感染、自身免疫性疾病和癌症进行开发。我们希望这些代理能够 在不久的将来，除了现有的 LAM 疗法之外，还可以提供新的治疗选择。

项目成果

How might endotyping guide chronic obstructive pulmonary disease treatment? Current understanding, knowledge gaps and future research needs.

• DOI: 10.1097/mcp.0000000000000751
• 发表时间: 2021-03-01
• 期刊: Current opinion in pulmonary medicine
• 影响因子: 3.3
• 作者: Burkes RM;Panos RJ;Borchers MT
• 通讯作者: Borchers MT

Increased Pulmonary GM-CSF Causes Alveolar Macrophage Accumulation. Mechanistic Implications for Desquamative Interstitial Pneumonitis.

肺 GM-CSF 增加导致肺泡巨噬细胞积聚。

• DOI: 10.1165/rcmb.2018-0294oc
• 发表时间: 2020
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Suzuki,Takuji;McCarthy,Cormac;Carey,BrennaC;Borchers,Michael;Beck,David;Wikenheiser-Brokamp,KathrynA;Black,Dianna;Chalk,Claudia;Trapnell,BruceC
• 通讯作者: Trapnell,BruceC