Immunobiology of Lung Fibrosis

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种进行性、致死性的间质性肺病。 IPF的发病机制尚不清楚，但一种常见的模式假定初始肺泡损伤，其触发炎症反应和纤维化。 某些T淋巴细胞亚群参与促进肺纤维化。 具体地，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的主要辅助性T 2型淋巴细胞（Th 2）应答（与Th 1应答相反）倾向于纤维化应答而不是修复。 此外，Th 2细胞因子刺激TGF-β的产生，TGF-β是一种关键的纤维化因子。在这个项目中，我们建议阐明T细胞同种型和它们的特征性细胞因子在动物肺纤维化中的作用。 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的鼠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。易感小鼠肺部的鼠γ疱疹病毒（MHV 68）感染将引起主要的Th 2淋巴细胞应答，并将引起持续和进行性肺纤维化。2. Th 1效应子功能缺陷和/或Th 2应答占优势易导致由博来霉素或γ疱疹病毒感染引起的肺纤维化的发展。3.肺细胞中的IL-4受体（IL-4 R α）信号传导途径介导TGF-β产生增加和肺纤维化。 为了验证这些假设，我们提出了以下具体目标：1。在B细胞缺陷小鼠中，确定博来霉素或用MHV 68感染肺对肺功能、组织病理学、肺胶原含量、Th 1和Th 2淋巴细胞应答以及全肺和肺衍生T淋巴细胞产生的细胞因子IL-4、IL-5、IL-13、IFN γ、TGF β的影响。2.确定特异性耗竭CD 4+和CD 8 + T细胞亚群对博莱霉素或MHV 68感染的肺反应的影响。3.采用过继转移体外极化的Th 1和Th 2细胞和偏向Th 1或Th 2应答的基因工程小鼠，以阐明T淋巴细胞应答与肺对博莱霉素或MHV 68感染的应答之间的关系。4.使用具有和不具有正常Th 2细胞的过继转移的IL-4受体缺陷小鼠，以确定除T淋巴细胞之外的细胞中的IL-4信号传导对于对MHV 68或博来霉素的肺纤维化应答是否重要。

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.