MECHANISMS OF LENTIVIRAL LYMPHOID INTERSTITIAL PNEUMONIA

慢病毒性淋巴细胞间质性肺炎的发病机制

• 批准号: 2231066
• 负责人: James C DeMartini
• 金额: $ 28.59万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2231066
• 关键词: CD4 molecule; CD8 molecule; MHC class I antigen; Retroviridae disease; T lymphocyte; antibody specificity; cytokine; disease /disorder model; genetic transcription; lung lavage; lymph; newborn animals; phenotype; sheep; tissue /cell culture; viral pneumonia; virus antigen; virus infection mechanism; virus protein

Pulmonary lymphoproliferative/infiltrative diseases are commonly associated with HIV infection of children and adults, and they often occur prior to the onset of AIDS. As its most common manifestation, ovine lentivirus (OvLV) infection of sheep induces lymphoid interstitial pneumonia (LIP) that is remarkably similar to HIV-associated pulmonary disease; similar histopathologically and in terms of lymphocyte phenotype . These lentiviruses also share similar morphology, genetic organization, capacity to undergo antigenic variation in vivo, and tropism for macrophages, including alveolar macrophages. Because of these similarities, we propose to use the OvLV model to investigate the mechanisms of induction and progression of lymphoid interstitial pneumonia (LIP). Two hypotheses, which are not mutually exclusive, will be tested: l) that lentiviral antigens, presented by MHC molecules, induce T cell proliferation, and 2) that recruitment of T cells contributes to the pulmonary infiltrative disease. To address the first hypothesis, three groups of newborn lambs will be injected intrabronchially with OvLV or sham-inoculated. T lymphocytes from broncho-alveolar fluid, lung lymph, and peripheral blood will be collected serially during acute and chronic stages of the disease process. The T cells collected from these sources from groups of lambs prior to infection and up to 6 months after infection will be phenotyped and analyzed for Vbeta gene heterogeneity and cytokine transcription. Cultures of T cells from the same compartments will be used to study viral antigen specificity, effector function, and MHC class I and class II restriction. If responding T cells are found to be oligoclonal, as assessed by analysis of the Vbeta gene repertoire, the role of viral antigens in driving T cell expansion will be examined. Alternatively, if the proliferating T cells are polyclonal, experiments will be designed to ascertain whether viral proteins act as superantigens. To address the second hypothesis, the capacity of labelled lung lymph T cells from acutely and chronically-infected animals to migrate from the bloodstream into the lung of the same animal or a recently-infected syngeneic twin will be studied. These experiments will provide information on the extent to which pulmonary recruitment and sequestration of activated T lymphocytes contributes to LIP in OvLV-infected animals. Elucidation of the mechanisms of T cell proliferation and pulmonary infiltration in lentivirus-infected sheep may lead to enhanced understanding of the pathogenesis of HIV-associated pulmonary disease and improved measures for its diagnosis, treatment and prevention.

肺淋巴增生性/浸润性疾病是常见的 与儿童和成人的艾滋病毒感染有关，而且它们经常发生 在艾滋病发作之前。作为其最常见的表现形式，绵羊 绵羊慢病毒感染诱导淋巴间质 肺炎(LIP)与HIV相关性肺非常相似 疾病；在组织病理学和淋巴细胞表型方面相似 。这些慢病毒也具有相似的形态、遗传组织、 在体内经历抗原变异的能力，以及对 巨噬细胞，包括肺泡巨噬细胞。正因为如此 相似性，我们建议使用OvLV模型来研究 淋巴间质性肺炎的发生发展机制 (嘴唇)。我们将检验两个并不相互排斥的假设： L)慢病毒抗原由MHC分子递呈，诱导T细胞 增殖，以及2)T细胞的招募有助于 肺部浸润性疾病。为了解决第一个假设，有三个 成群的新生羔羊将被气管内注射OvLV或 假接种。从支气管肺泡液、肺淋巴、 并在急慢性疾病期间连续采集外周血液 疾病过程的各个阶段。从这些来源收集的T细胞 感染前和感染后最多6个月的羊群 将对Vbeta基因异质性和细胞因子进行表型和分析 抄写。来自相同隔室的T细胞培养将是 用于研究病毒抗原的特异性、效应器功能和MHC分类 一级和二级限制。如果发现有反应的T细胞 寡克隆，通过分析Vbeta基因谱系进行评估， 将研究病毒抗原在驱动T细胞增殖中的作用。 或者，如果增殖的T细胞是多克隆的，实验 将被设计用来确定病毒蛋白是否作为超抗原。 为了解决第二个假设，标记肺淋巴T细胞的能力 来自急性和慢性感染动物的细胞从 同一动物或最近感染的动物的血液流入肺 将对同基因双胞胎进行研究。这些实验将提供信息 关于肺重新募集和隔离的程度 活化的T淋巴细胞参与了OvLV感染动物的LIP。 T细胞增殖与肺损伤机制的研究进展 慢病毒感染绵羊体内的渗透可能导致增强 对HIV相关性肺部疾病发病机制的认识 改进其诊断、治疗和预防措施。