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、致死性间质性肺疾病。IPF的发病机制还不是很清楚，但一个常见的范例假设最初的肺泡损伤，它触发了炎症反应和纤维化。T淋巴细胞的某些亚群被认为与促进肺纤维化有关。具体地说，以辅助性T细胞为主的2型淋巴细胞(Th2)反应具有由IL-4、IL-5、IL-10和IL-13产生的特征细胞因子谱(与Th1反应相反)，倾向于纤维化反应而不是修复。此外，Th2细胞因子刺激转化生长因子-β的产生，这是一种关键的纤维化因子。在这个项目中，我们建议阐明T细胞亚型及其特有的细胞因子在动物肺纤维化中的作用。我们将在啮齿动物博莱霉素模型和我们认为与人类疾病相关的一种新的小鼠伽马疱疹病毒模型中进行平行研究。因此，我们提出以下假设：1.小鼠γ疱疹病毒(MHV68)感染易感小鼠的肺部，可引起以Th2为主的淋巴细胞反应，并可引起持续性和进行性肺纤维化。2.Th1效应器功能缺陷和/或Th2应答占优势是博莱霉素或伽玛疱疹病毒感染所致肺纤维化的易感因素。3.肺细胞内IL-4受体(IL-4Rα)信号通路介导了转化生长因子-β的产生增加和肺纤维化。1.在B细胞缺陷小鼠中，观察博莱霉素或MHV68肺部感染对肺功能、组织病理学、肺组织胶原含量、Th1、Th2淋巴细胞反应及细胞因子IL-4、IL-5、IL-13、干扰素-γ、转化生长因子β的影响。2.探讨CD4+、CD8+T细胞亚群特异性耗竭对博莱霉素或MHV68感染所致肺组织反应的影响。3.通过过继转移体外极化的Th1和Th2细胞和偏向Th1或Th2应答的基因工程小鼠，阐明T淋巴细胞应答与肺部对博莱霉素或MHV68感染的应答之间的关系。4.利用过继转移正常Th2细胞和不过继转移正常Th2细胞的IL-4受体缺陷小鼠，确定T淋巴细胞以外的细胞中的IL-4信号是否在MHV68或博莱霉素引起的肺纤维化反应中起重要作用。

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.