Immunobiology of Lung Fibrosis

肺纤维化的免疫生物学

• 批准号: 6732687
• 负责人: Ana Lucia Mora
• 金额: $ 12.57万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-04 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732687
• 关键词: B lymphocyte; Gammaherpesvirinae; bleomycin; collagen; cytokine; cytokine receptors; helper T lymphocyte; histopathology; idiopathic pulmonary fibrosis; immunopathology; immunoregulation; interleukin 4; laboratory mouse; passive immunization; respiratory infections; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, lethal form of interstitial lung disease. The pathogenesis of IPF is not well understood but a common paradigm postulates an initial alveolar injury, which triggers an inflammatory response and fibrosis. Certain subsets of T lymphocytes have been implicated in promoting lung fibrogenesis. Specifically, a predominantly T helper type 2 lymphocyte (Th2) response with the characteristic cytokine profile consisting of IL-4, IL-5, IL-10 and IL-13 production (as opposed to a Th1 response) predisposes towards a fibrotic response rather than repair. In addition, Th2 cytokines stimulate the production of TGF-beta, a critical fibrogenic factor. In this project, we propose to clarify the roles of T cell isotypes and their characteristic cytokines on lung fibrosis in animals. We will conduct parallel studies in the rodent bleomycin model and in a new murine gamma herpesvirus model that we believe relevant to the human disease. Therefore, we propose the following hypotheses: 1. Murine gamma herpesvirus (MHV68) infection of the lungs of susceptible mice will cause a predominantly Th2 lymphocyte response and will cause persistent and progressive pulmonary fibrosis. 2. Defective Th1 effector function and/or a predominance of Th2 responses predisposes to the development of lung fibrosis caused by either bleomycin or gamma herpesvirus infection. 3. The IL-4 receptor (IL-4Ralpha) signaling pathway in lung cells mediates increased TGF-beta production and lung fibrosis. To test these hypotheses, we propose the following specific aims: 1. In B cell deficient mice, to determine effects of bleomycin or infection of the lungs with MHV68 on lung function, histopathotogy, lung collagen content, Th1 and Th2 lymphocyte responses and cytokine ILL-4, IL-5, IL-13, IFNgamma, TGFbeta) production by whole lung and lung-derived T lymphocytes. 2. To determine effects of specific depletion of CD4+ and CD8+ T cell subsets on pulmonary responses to bleomycin or MHV68 infection. 3. Using adoptive transfer of in vitro polarized Th1 and Th2 cells and genetically engineered mice biased toward Th1 or Th2 responses, to clarify relationships between the T-lymphocyte responses and responses of the lungs to bleomycin or MHV68 infection. 4. Using IL-4 receptor deficient mice with and without adoptive transfer of normal Th2 cells, to determine whether IL-4 signaling in cells other than T lymphocytes is important to the lung fibrogenic response to MHV68 or bleomycin.

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种进行性、致命性的间质性肺疾病。 IPF 的发病机制尚不清楚，但常见的范式假设最初的肺泡损伤，从而引发炎症反应和纤维化。 T 淋巴细胞的某些亚群与促进肺纤维化有关。 具体来说，主要是 T 辅助 2 型淋巴细胞 (Th2) 反应，具有由 IL-4、IL-5、IL-10 和 IL-13 产生组成的特征性细胞因子谱（与 Th1 反应相反），倾向于纤维化反应而不是修复。 此外，Th2 细胞因子刺激 TGF-β 的产生，TGF-β 是一种关键的纤维形成因子。在这个项目中，我们建议阐明 T 细胞同种型及其特征细胞因子对动物肺纤维化的作用。 我们将在啮齿动物博来霉素模型和我们认为与人类疾病相关的新鼠γ疱疹病毒模型中进行平行研究。 因此，我们提出以下假设： 1. 鼠γ疱疹病毒（MHV68）感染易感小鼠的肺部将引起以Th2淋巴细胞为主的反应，并导致持续性和进行性肺纤维化。 2. Th1 效应器功能缺陷和/或 Th2 反应占主导地位容易发生由博莱霉素或 γ 疱疹病毒感染引起的肺纤维化。 3.肺细胞中的IL-4受体(IL-4Rα)信号通路介导TGF-β产生增加和肺纤维化。 为了检验这些假设，我们提出以下具体目标： 1. 在 B 细胞缺陷小鼠中，确定博莱霉素或 MHV68 肺部感染对肺功能、组织病理学、肺胶原含量、Th1 和 Th2 淋巴细胞反应以及全肺细胞因子 ILL-4、IL-5、IL-13、IFNgamma、TGFbeta) 产生的影响 和肺源性T淋巴细胞。 2. 确定特异性去除 CD4+ 和 CD8+ T 细胞亚群对博来霉素或 MHV68 感染的肺部反应的影响。 3. 利用体外极化的 Th1 和 Th2 细胞以及偏向 Th1 或 Th2 反应的基因工程小鼠的过继转移，阐明 T 淋巴细胞反应与肺部对博莱霉素或 MHV68 感染的反应之间的关系。 4.使用具有或不具有正常Th2细胞过继转移的IL-4受体缺陷型小鼠，以确定T淋巴细胞以外的细胞中的IL-4信号传导对于MHV68或博莱霉素的肺纤维化反应是否重要。