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.

项目概要 巨细胞肺炎（GCP）是一系列致命的慢性疾病，包括硬金属肺 疾病、病毒相关 GCP 和非硬金属、非传染性 GCP。无论 病因学上，GCP 的特点是存在肺泡巨噬细胞衍生的多核细胞 巨细胞（MGC）与其他免疫浸润一起阻塞肺泡腔并导致 肺衰竭。对于 GCP 的发病机制知之甚少，这很大程度上是由于缺乏 合适的动物模型，并且没有有效的治疗方法，提出了关键知识 差距。在这个提案中，我们将通过使用一种独特的动物来弥补这一知识差距的一个方面 我们最近开发的 GCP 模型是为了研究导致 这种致命的疾病。硬金属（如钴）工人的血清 IgE（CD4+）水平升高 T辅助细胞（TH）2细胞依赖性抗体同种型，以及含有硬金属GCP的患者 支气管肺泡灌洗液 (BALF) 中 T 细胞数量增加，表明 T 细胞在 GCP 病理学中的潜在作用。然而，目前尚不清楚失调是如何发生的 TH 细胞的减少导致 MGC 形成，从而导致 GCP 的发展。我们的长期目标是 剖析 GCP 发病机制；这些发现可能会带来新奇的结果 治疗选择。该提议的科学前提得到了我们的大力支持 初步研究表明，CIS 是细胞因子信号传导抑制因子 (SOCS) 家族的成员， 需要抑制 GCP，这可能是通过 T 细胞依赖性方式进行的；小鼠顺式缺陷 导致 MGC 的形成和积累，同时肺部 TH 细胞数量增加 并导致肺泡严重阻塞，甚至导致死亡。我们的中心假设是 CIS 通过限制 TH 细胞反应来抑制 MGC 形成，从而防止 GCP。具体 目标是： 目标 1. 确定 CIS 在 GCP 发展中的 TH 细胞内在作用。目标2。 描绘 GCP 中 CIS 抑制功能的潜在机制，尤其是硬性机制 金属肺病。