CHEMOKINES IN LUNG DISEASE OF HIV1 TRANSGENIC MICE

该研究的长期目标是研究趋化因子及其受体在淋巴细胞性间质性肺炎发病机制中的作用。淋巴细胞性间质性肺炎是在特定免疫细胞(未成熟的CD4CD8T细胞、成熟的CD4T细胞和巨噬细胞/树突状细胞系的细胞)中表达部分HIV-1基因的转基因小鼠中发展起来的。我们的中心假设是这种肺部疾病是由免疫介导的，并通过特定的趋化因子的作用在肺内招募免疫细胞。在感染了HIV-1并患有淋巴细胞性间质性肺炎的人中，在肺部发现的主要免疫细胞群是CD8T细胞。由于这些转基因小鼠的肺部病变与许多其他表型非常相似，与感染HIV-1的人类非常相似，我们假设这种肺部疾病模型与人类，特别是儿童的与HIV-1相关的淋巴细胞性间质性肺炎有关。为了了解这种肺部疾病的发病机制，我们打算：1-鉴定和定量肺内的免疫细胞。2-确定这些小鼠是否表现出有利于特定免疫细胞归巢的特定肺微环境。3-鉴定这些转基因小鼠肺中产生的趋化因子。4-确定阻断或删除特定的趋化因子或其受体以及过度表达某些趋化因子受体是否会改变淋巴细胞性间质性肺炎的发展。

The long term objective of the research proposal is to study the role of chemokines and their receptors in the pathogenesis of lymphocytic interstitial pneumonitis which develop in transgenic mice expressing some of the HIV-1 genes in specific immune cells (immature CD4+CD8+ T cells, mature CD4+ T cells and cells of the macrophage/dendritic lineage. Our central hypothesis is that this lung disease is immune-mediated and is driven by the recruitment of immune cells in the lung through the action of specific chemokines. In humans infected with HIV-1 and having lymphocytic interstitial pneumonitis, the main population of immune cells found in the lung are the CD8+ T cells. Because the lung lesions of these Tg mice are associated with many other phenotypes very similar to those found in humans infected with HIV-1, we postulate that this model of lung disease is relevant to the lymphocytic interstitial pneumonitis associated with HIV-1 in humans, especially in children. To understand the pathogenesis of this lung disease, we intend: 1- To identify and quantitate the immune cells in the lung. 2- To determine whether these mice exhibit a specific lung microenvironment favoring homing of specific immune cells. 3- To identify the chemokines produced in the lung of these Tg mice. 4- To determine whether blocking or deleting specific chemokines or their receptors and overexpressing some chemokine receptors alter the development of lymphocytic interstitial pneumonitis.