The Cytokine Suppressor CIS in Giant Cell Pneumonitis

项目摘要 巨细胞性肺炎是一组致死性慢性疾病，包括硬金属肺 疾病、病毒相关GCP和非硬金属、非感染性GCP。无论 在病因学方面，GCP的特征是存在肺泡巨噬细胞源性多核 巨细胞（MGCs）与其他免疫浸润物一起阻塞肺泡腔， 肺衰竭GCP的发病机制知之甚少，这主要是由于缺乏 适当的动物模型，并且没有有效的治疗方法，提出了关键的知识 间隙在这个提议中，我们将通过使用一种独特的动物来缩小这种知识差距的一个方面 我们最近开发的GCP模型，以研究导致 这种致命的疾病。硬金属（如钴）工人血清IgE水平升高，CD 4 + 辅助性T细胞（TH）2细胞依赖性抗体同种型，和硬金属GCP患者含有 支气管肺泡灌洗液（BALF）中的T细胞数量增加，提示 T细胞在GCP病理学中的潜在作用。然而，完全不清楚失调是如何 TH细胞的活化导致MGC的形成，从而导致GCP的发展。我们的长期目标是 剖析GCP发病机制的潜在机制;这些发现可能会导致新的 治疗选择这一建议的科学前提得到了我们的大力支持。 初步研究表明，CIS是细胞因子信号转导抑制因子（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;小鼠中的顺式缺陷 导致MGCs的形成和积累，并增加肺中TH细胞的数量 造成肺泡严重阻塞，甚至死亡。我们的核心假设是， 通过限制TH细胞反应抑制MGC形成，从而防止GCP。具体 目标：目标1。确定TH细胞-CIS在GCP发展中的内在作用。目标二。 阐明CIS在GCP中抑制作用的机制，特别是难 金属肺病

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.