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: 10372043
• 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/10372043
• 关键词: Address; Allergic; Alveolar; Alveolar Macrophages; Alveolus; 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 diseases; Modernization; Molecular; Mus; Obstruction; Occupational Diseases; Occupational Exposure; Particulate; Pathogenesis; Pathology; Patients; Physiology; Pilot Projects; Play; Pulmonary Inflammation; Regulation; Respiratory Disease; 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 巨细胞肺炎（GCP）是致命慢性疾病的集合，包括硬金属肺 疾病，与病毒相关的GCP和非硬质金属，非感染GCP。不管是什么 病因，GCP的特征是存在肺泡巨噬细胞衍生的多核 巨细胞（MGC）与其他免疫浸润阻塞肺泡空间并引起 肺部衰竭。 GCP的发病机理知之甚少，这主要是由于缺乏 适当的动物模型，也没有有效的治疗 差距。在此提案中，我们将通过使用独特的动物来弥补这一知识差距的一个方面 GCP的模型我们最近开发用于研究导致的免疫机制 这种致命疾病。硬金属（例如钴）工人的血清IgE水平升高，CD4+ T助手（Th）2个细胞依赖性抗体同种型，硬金属GCP的患者包含 支气管肺泡灌洗液（BALF）中T细胞数量增加，暗示 T细胞在GCP病理中的潜在作用。但是，完全不清楚如何失调 Th细胞的导致MGC形成，导致GCP的发展。我们的长期目标是 剖析GCP发病机理的基础机制；这些发现可能导致新颖 治疗选择。我们的科学前提得到了我们的强烈支持 初步研究，CIS是细胞因子信号传导（SOCS）家族抑制器的成员， 需要抑制GCP，这可能是通过T细胞依赖性方式进行的；小鼠的顺式缺陷 导致肺中TH细胞数量增加的MGC的形成和积累 并引起严重的肺泡阻塞，甚至导致死亡。我们的中心假设是顺式 通过限制TH细胞反应抑制MGC形成，因此可以防止GCP。具体 目的是：目标1。确定CI在GCP发展中的第三个细胞中性作用。目标2。 描述CI在GCP中抑制功能的机制，尤其是硬 金属肺病。