Pulmonary CD4+ T-Cell Repopulation in Immune Reconstitu*

免疫重建中的肺 CD4 T 细胞增殖*

• 批准号: 7126010
• 负责人: KENNETH S KNOX
• 金额: $ 36.32万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126010
• 关键词: AIDS; AIDS therapy; antiviral agents; bronchoscopy; cell population study; clinical research; combination chemotherapy; computed axial tomography; cytokine; disease /disorder proneness /risk; enzyme linked immunosorbent assay; flow cytometry; helper T lymphocyte; human subject; iatrogenic disease; immunopathology; leukocyte count; longitudinal human study; medical complication; outcomes research; polymerase chain reaction; respiratory infections; spirometry; therapy adverse effect

DESCRIPTION (provided by applicant): Most patients with Human Immunodeficiency Virus (HIV) infection will have a pulmonary complication at some point during the course of their disease. The advent of highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of pulmonary infections. Although infections still predominate, some patients have a paradoxical worsening after initiation of HAART despite evidence of a recovering immune system. This phenomenon is termed immune restoration disease (IRD) and can affect up to 25% of patients who initiate HAART. IRD can be fatal and frequently mimics active pulmonary infection. As such, it can be a difficult diagnosis and contribute to morbidity and excessive clinical testing. Early pulmonary IRD is usually caused by latent or unrecognized infections at the time HAART is initiated. These infectious agents provide the substrate for the immunopathological response in IRD. However, late pulmonary IRD frequently manifests as sarcoidosis and is caused by unknown antigens. Stratifying people at risk for IRD and assessing their long term outcome is thus increasingly important, especially as the number of patients treated with HAART increases worldwide. We hypothesize that pulmonary IRD is clinically underrecognized and mediated by unbalanced Th1 responses. We propose to address this hypothesis by performing sequential CT scans, clinical assessment and bronchoscopies to harvest lung T cells in patients starting HAART therapy. Cytokine measurements, flow cytometry, and TREC analysis will be performed on lung and blood T cell subsets to assess if naive or memory cells are responsible for Th1-mediated IRD. Specific aims include: 1. To define a large, well-characterized clinical cohort of HIV-infected subjects for longitudinal study of IRD. 2. To determine the mechanisms of CD4 repopulation of the lung and 3. To define predictors of early and late pulmonary IRD based on clinical and immunological parameters. This work will have significant implications on clinical issues in HIV infected subjects, including predicting who is at risk for IRD and the 3 year outcome of patients with IRD. These studies also will provide the immunologic foundation for treatment strategies. Public Health Statement: As more patients worldwide are treated with anti-HIV drugs, the "side effects" of these drugs require study. Patients who are at risk for these therapy-related problems need to know if their long term health is affected.

描述（由申请人提供）： 大多数人类免疫缺陷病毒 (HIV) 感染患者在病程中的某个时刻会出现肺部并发症。高效抗逆转录病毒疗法（HAART）的出现极大地降低了肺部感染的发生率。尽管感染仍然占主导地位，但一些患者在开始HAART后病情却出现了矛盾的恶化，尽管有证据表明免疫系统正在恢复。这种现象被称为免疫恢复疾病 (IRD)，可能影响高达 25% 开始 HAART 的患者。 IRD 可能是致命的，并且经常类似于活动性肺部感染。因此，这可能是一个困难的诊断，并导致发病率和过度的临床检测。早期肺部IRD通常是由HAART开始时潜伏或未被识别的感染引起的。这些感染因子为 IRD 中的免疫病理反应提供了底物。然而，晚期肺部 IRD 经常表现为结节病，并且由未知抗原引起。因此，对 IRD 风险人群进行分层并评估他们的长期结果变得越来越重要，特别是随着全球范围内接受 HAART 治疗的患者数量不断增加。我们假设肺部 IRD 在临床上未被充分认识，并且是由不平衡的 Th1 反应介导的。我们建议通过连续 CT 扫描、临床评估和支气管镜检查来解决这一假设，以收集开始 HAART 治疗的患者的肺 T 细胞。将对肺和血液 T 细胞亚群进行细胞因子测量、流式细胞术和 TREC 分析，以评估幼稚细胞或记忆细胞是否导致 Th1 介导的 IRD。具体目标包括： 1. 定义一个大型的、特征明确的 HIV 感染者临床队列，用于 IRD 的纵向研究。 2. 确定肺部 CD4 重新增殖的机制，以及 3. 根据临床和免疫学参数确定早期和晚期肺部 IRD 的预测因素。这项工作将对 HIV 感染者的临床问题产生重大影响，包括预测谁有 IRD 风险以及 IRD 患者的 3 年结果。这些研究还将为治疗策略提供免疫学基础。公共卫生声明：随着全世界越来越多的患者接受抗艾滋病毒药物治疗，这些药物的“副作用”需要研究。面临这些治疗相关问题风险的患者需要知道他们的长期健康是否受到影响。