Interferon-gamma in Experimental Pulmonary Fibrosis

实验性肺纤维化中的干扰素-γ

• 批准号: 6629468
• 负责人: RICHARD I ENELOW
• 金额: $ 32.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629468
• 关键词: CD8 molecule; SCID mouse; T cell receptor; alveolar macrophages; antigen presenting cell; apoptosis; cell population study; chronic disease /disorder; cytokine receptors; cytotoxic T lymphocyte; disease /disorder model; inflammation; interferon gamma; laboratory mouse; lung injury; passive immunization; pathologic process; pulmonary fibrosis /granuloma; respiratory epithelium

DESCRIPTION (provided by applicant): Chronic fibrotic lung disease occurs in a variety of clinical settings, including the idiopathic interstitial pneumonias, as well as in many of the rheumatic diseases. We previously developed a model of acute T cell-mediated pulmonary injury, which results in severe alveolar injury, leading to significant respiratory impairment and death within a few days. This model involves the adoptive transfer of activated CD8+ T cells into recipient animals expressing the specific antigen on alveolar epithelial cells. In contrast with the acute lung injury occurring after transfer of wild-type CD8+ T cells, we have recently found that chronic inflammation and fibrosis may result from the CD8+ T cell recognition of alveolar antigen in the absence of IFN-gamma exclusively in the antigen-specific cell population, and have found that these T cells induce a totally different pattern of lung injury, including a more chronic pattern of inflammation and, importantly, interstitial and intraluminal fibrosis. This was accomplished by using IFN-gamma-deficient CD8+ T cell clones for adoptive transfer, which results in inflammation and fibrosis that evolves over a period of 2-4 weeks after administration. This very exciting result represents the first animal model of pulmonary fibrosis that does not involve an exogenous toxin, and which evolves entirely from a single, well-defined molecular interaction, the T cell receptor recognition of antigen on alveolar epithelial cells. In order to understand the mechanisms which underly the resolution of acute pulmonary inflammation which results directly from expression of IFN-gamma by the antigen-specific CD8+ T cell, and the factors which may lead to chronic inflammation and fibrosis in its absence, we propose the following Specific Aims:1. To characterize the impact of IFN-gamma expressed by CD8+ T cells on input and host T lymphocyte activities in vivo.2. To characterize the specific effects of IFN-gamma expressed by CD8+ T cells on host macrophages and the impact on progression to chronic pulmonary inflammation.3. To characterize the specific effects of CD8+ T cell recognition in the absence of IFN-gamma on antigen-presenting epithelial cells and the impact on progression to chronic pulmonary inflammation.

描述（由申请人提供）：慢性纤维化肺病发生在各种临床环境中，包括特发性间质性肺炎以及许多风湿性疾病。 我们先前开发了一种急性T细胞介导的肺损伤模型，该模型导致严重的肺泡损伤，导致显著的呼吸障碍并在几天内死亡。 该模型涉及将活化的CD 8 + T细胞过继转移到在肺泡上皮细胞上表达特异性抗原的受体动物中。 与野生型CD 8 + T细胞转移后发生的急性肺损伤相反，我们最近发现慢性炎症和纤维化可能是由于在抗原特异性细胞群中不存在IFN-γ的情况下CD 8 + T细胞识别肺泡抗原所致，并且发现这些T细胞诱导完全不同的肺损伤模式，包括更慢性的炎症模式，重要是间质和腔内纤维化。 这是通过使用IFN-γ缺陷型CD 8 + T细胞克隆进行过继转移来实现的，这导致炎症和纤维化在给药后2-4周的时间内发展。 这一非常令人兴奋的结果代表了第一个不涉及外源性毒素的肺纤维化动物模型，并且完全从单一的、明确定义的分子相互作用演变而来，即肺泡上皮细胞上抗原的T细胞受体识别。 为了理解由抗原特异性CD 8 + T细胞表达IFN-γ直接导致的急性肺部炎症消退的机制，以及在其缺乏的情况下可能导致慢性炎症和纤维化的因素，我们提出以下具体目的：1.目的：1.研究CD 8 + T细胞表达IFN-γ对体内输入和宿主T淋巴细胞活性的影响.研究CD 8 + T细胞表达的IFN-γ对宿主巨噬细胞的特异性作用及其对慢性肺部炎症进展的影响.表征在IFN-γ不存在的情况下CD 8 + T细胞识别对抗原呈递上皮细胞的特异性作用以及对慢性肺部炎症进展的影响。