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

基本信息

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
项目类别：
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

项目摘要

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。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透到肺部，导致平滑肌细胞的破坏。不幸的是，医生通常会诊断周围肺组织、囊性重塑和器官衰竭。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可以定义这些细胞在晚期疾病以及疾病早期阶段的作用。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。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，具体而言，循环系统和肺中存在独特的 NK 细胞亚群，这可能与 LAM 发病机制有关。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。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会下调 NKG2D 表达并损害 NK 细胞功能。在整个发病机制中动态塑造 NK 细胞表型和功能。提案是使用两名 LAM 患者来定义 NK 细胞和 NKG2D 在 LAM 中的表型、功能和作用为了实现这一目标，我们将 1) 定义独特 NK 细胞的功能意义。 LAM 中的群体。 2) 定义 VEGFD 扩增的 NK 细胞激活机制。 NK 细胞和 Nkg2d 在 LAM 的启动和进展中的作用以及 4) 定义功效和益处。循环可溶性 Nkg2d 配体的治疗性抑制可能会成功完成这些研究。对我们理解 LAM 发病机制有很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 配体的干预有几种旨在调节 NK 细胞功能的疗法。我们希望这些药物能够治疗慢性感染、自身免疫性疾病和癌症。在不久的将来，除了 LAM 的现有疗法之外，还可以提供新的治疗选择。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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