The Cytokine Suppressor CIS in Giant Cell Pneumonitis

巨细胞肺炎中的细胞因子抑制因子 CIS

• 批准号: 10133137
• 负责人: Xuexian Yang
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133137
• 关键词: Address; Allergic; Alveolar; Alveolar Macrophages; Animal Genetics; Animal Model; Antibodies; Antigen Presentation; Biology; Bronchoalveolar Lavage Fluid; CISH gene; Cell Differentiation process; Cells; Cellular biology; Cessation of life; Chronic Disease; Cobalt; Collection; Core Facility; Cytokine Signaling; Data; Development; Disease; Environment; Etiology; Exposure to; Family; Genetic; Giant Cells; Goals; Health Sciences; Helper-Inducer T-Lymphocyte; Human; IgE; Immune; Immunologics; Knowledge; Lead; Lung; Lung Inflammation; Lung diseases; Modernization; Molecular; Mus; Obstruction; Occupational Diseases; Occupational Exposure; Particulate; Pathogenesis; Pathology; Patients; Physiology; Pilot Projects; Play; Pulmonary Inflammation; Regulation; Respiratory Failure; Role; STAT3 gene; STAT6 gene; Serum; Signal Transduction; Stat5 protein; T cell response; T-Lymphocyte; Th2 Cells; Tumor-infiltrating immune cells; Virus; Work; cytokine; effective therapy; hard metal; immunotoxicity; macrophage; member; novel; novel therapeutics; polarized cell; prevent; public health relevance; response; tungsten carbide

Project Summary Giant cell pneumonitis (GCP) is a collection of fatal chronic diseases, including hard metal lung disease, virus-associated GCP and non-hard metal, non-infectious GCP. Regardless of the etiology, GCP is characterized by the presence of alveolar macrophage-derived multinucleate giant cells (MGCs) that together with other immune infiltrates obstruct alveolar spaces and cause lung failure. Little is known on the pathogenesis of GCP, which is largely due to lack of appropriate animal models, and there is no effective treatment, presenting a critical knowledge gap. In this proposal, we will close an aspect of this knowledge gap by using a unique animal model of GCP we recently developed to investigate the immunological mechanisms that lead to this fatal disease. Hard metal (such as cobalt) workers had elevated levels of serum IgE, a CD4+ T helper (TH) 2 cell-dependent antibody isotype, and patients with hard metal GCP contained increased numbers of T cells in their bronchoalveolar lavage fluids (BALFs), implicating a potential role of T cells in the pathology of GCP. However, it is entirely unclear how dysregulation of TH cells causes MGC formation, resulting in the development of GCP. Our long-term goal is to dissect the mechanisms underlying the pathogenesis of GCP; the discoveries may lead to novel therapeutic options. The scientific premise of this proposal is strongly supported by our preliminary studies that CIS, a member of the suppressor of the cytokine signaling (SOCS) family, is required to suppress GCP, which is likely via a T cell-dependent manner; Cis-deficiency in mice leads to formation and accumulation of MGCs with increased numbers of TH cells in the lungs and causes severe obstruction of alveoli, leading to even death. Our central hypothesis is that CIS inhibits MGC formation via restricting TH cell responses, therefore preventing GCP. The Specific Aims are: Aim 1. Determine the TH cell-intrinsic role of CIS in the development of GCP. Aim 2. Delineate the mechanism underlying the suppressive function of CIS in GCP, especially hard metal lung disease.

项目摘要 巨细胞性肺炎(GCP)是一组致命性慢性疾病，包括硬金属肺。 疾病、病毒相关的GCP和非硬金属、非传染性GCP。不管是什么 在病因学上，GCP的特征是肺泡巨噬细胞来源的多核细胞的存在 巨细胞(MGCs)与其他免疫浸润物一起阻塞肺泡腔并导致 肺功能衰竭。GCP的发病机制目前知之甚少，这主要是由于缺乏 合适的动物模型，没有有效的治疗方法，呈现出批判性的知识 差距。在这个提案中，我们将通过使用一种独特的动物来弥合这种知识鸿沟的一个方面 我们最近开发了一种GCP模型，以研究导致 这种致命的疾病。硬质合金(如钴)工人的血清IgE水平升高，即CD4+ T辅助(TH)2细胞依赖抗体亚型和硬金属GCP患者包含 其支气管肺泡灌洗液(BALF)中T细胞数量增加，表明 T细胞在GCP发病机制中的潜在作用然而，目前还完全不清楚监管失衡是如何 TH细胞导致MGC的形成，导致GCP的发生。我们的长期目标是 剖析GCP的发病机制；这些发现可能导致新的 治疗选择。这项建议的科学前提得到了我们的大力支持 初步研究表明，细胞因子信号转导抑制因子(SOCS)家族中的一员--CIS， 需要抑制GCP，这可能是通过T细胞依赖的方式；小鼠的顺式缺乏 导致MGCS的形成和积聚，同时肺中TH细胞数量增加 并导致严重的肺泡阻塞，甚至死亡。我们的中心假设是独联体 通过限制TH细胞的反应来抑制MGC的形成，从而防止GCP。具体的 目的：目的1.确定TH细胞在GCP发生发展中的内在作用。目标2. 阐明在GCP中CIS抑制作用的潜在机制，尤其是Hard 金属肺病。