CHEMOKINES IN LUNG DISEASE OF HIV1 TRANSGENIC MICE

该研究计划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，该疾病发生在表达特定免疫细胞（未成熟CD 4 + CD 8 + T细胞、成熟CD 4 + T细胞和巨噬细胞/树突细胞系细胞）中某些HIV-1基因的转基因小鼠中。 我们的中心假设是，这种肺部疾病是免疫介导的，并通过特定趋化因子的作用在肺部招募免疫细胞来驱动。 在感染HIV-1并患有淋巴细胞性间质性肺炎的人中，在肺中发现的主要免疫细胞群体是CD 8 + T细胞。 由于这些Tg小鼠的肺部病变与许多其他表型非常相似，发现在人类感染HIV-1，我们推测，这种模式的肺部疾病是相关的淋巴细胞间质性肺炎与HIV-1在人类，特别是在儿童。为了了解这种肺部疾病的发病机制，我们打算：1-鉴定和定量肺中的免疫细胞。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Tg小鼠肺中产生的趋化因子。4-确定阻断或删除特定趋化因子或其受体以及某些趋化因子受体的过表达是否改变淋巴细胞性间质性肺炎的发生。

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.