Pulmonary CD4+ T-Cell Repopulation in Immune Reconstituion Syndrome

免疫重建综合征中的肺 CD4 T 细胞增殖

• 批准号: 7448545
• 负责人: KENNETH S KNOX
• 金额: $ 30.24万
• 依托单位: UNIVERSITY OF ARIZONA
• 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/7448545
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adverse drug effect; Affect; Alveolar; Alveolitis; Antigens; Autoimmune Process; Blood; Blood Vessels; Bronchoscopy; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD4/CD8 ratio procedure; Caring; Cell Count; Cell Death; Cell physiology; Cells; Clinical; Clinical Trials; Clinical assessments; Complication; Cytomegalovirus; Data; Diagnosis; Diagnostic; Disease; Disease Progression; Enrollment; Environment; Equilibrium; Flow Cytometry; Foundations; Frequencies; Genetic Polymorphism; Genotype; HIV; Harvest; Health; Highly Active Antiretroviral Therapy; Human; Image; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Immunosuppression; Incidence; Infection; Infectious Agent; Inflammatory; Inflammatory Response; Longitudinal Studies; Lung; Lymphocyte; MHC Class II Genes; Measurement; Mediating; Memory; Modeling; Morbidity - disease rate; Mycobacterium tuberculosis; Numbers; Opportunistic Infections; Outcome; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Process; Prophylactic treatment; Prospective Studies; Protocols documentation; Public Health; Rate; Reaction; Research Personnel; Resolution; Risk; Risk Factors; Role; Sarcoidosis; Site; Subgroup; Syndrome; T-Cell Receptor-Rearrangement Excision DNA Circles; T-Lymphocyte; T-Lymphocyte Subsets; Th1 Cells; Therapeutic immunosuppression; Time; Tissues; Uveitis; Viral Load result; Virus Diseases; Work; X-Ray Computed Tomography; antiretroviral therapy; base; clinical phenotype; cohort; cytokine; follow-up; novel; pathogen; programs; prospective; reconstitution; research clinical testing; response; restoration; trend

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）感染患者在疾病过程中的某个时候会出现肺部并发症。高效抗逆转录病毒疗法（HAART）的出现大大降低了肺部感染的发病率。尽管感染仍然占主导地位，但一些患者在开始HAART后出现矛盾的恶化，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），可影响高达25%的开始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，它可能是一个困难的诊断，并有助于发病率和过度的临床试验。早期肺部IRD通常是由HAART开始时的潜伏或未识别的感染引起的。这些感染因子为IRD中的免疫病理学应答提供了底物。然而，晚期肺IRD经常表现为结节病，由未知抗原引起。因此，对IRD风险人群进行分层并评估其长期结果变得越来越重要，特别是随着全球接受HAART治疗的患者数量的增加。我们假设肺IRD在临床上被低估，并由不平衡的Th1应答介导。我们建议通过进行连续CT扫描、临床评估和支气管镜检查来解决这一假设，以在开始HAART治疗的患者中收获肺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，以评估初始或记忆细胞是否负责Th1介导的IRD。具体目标包括： 1.为IRD的纵向研究确定一个大型的、特征良好的HIV感染受试者临床队列。2.探讨肺组织CD4再增殖的机制。根据临床和免疫学参数确定早期和晚期肺IRD的预测因子。这项工作将对HIV感染受试者的临床问题产生重大影响，包括预测IRD的风险和IRD患者的3年结局。这些研究也将为治疗策略提供免疫学基础。公共卫生声明：随着全球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。有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。