Altered Dendritic Cell Function in Sarcoidosis Anergy

结节病无反应中树突状细胞功能的改变

• 批准号: 6919980
• 负责人: STEPHEN J OLIVER
• 金额: $ 29.58万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-09 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919980
• 关键词: anergy; cellular immunity; clinical research; dendritic cells; flow cytometry; helper T lymphocyte; human subject; immune response; ionomycin; phenotype; phorbols; sarcoidosis

DESCRIPTION (provided by applicant): Sarcoidosis is a disease of unknown etiology characterized by persistent granulomas with damage to surrounding tissues. Despite the presence of focal inflammation, sarcoidosis patients frequently have partial or complete anergy to common skin reactants, along with other evidence of suppressed systemic cellular immunity. Evidence suggests that dendritic cells (DCs), key regulators of cellular immunity, could contribute to anergy in sarcoidosis. The type of T cell response induced by DCs after uptake and presentation of antigen depends on the DC subset and maturation stage. Mature DCs primarily induce Thl-type responses critical for effector T cell responses, macrophage activation and delayed-type hypersensitivity. However, immature DCs of either subset can induce T cell anergy, resulting in impaired T cell responses and decreased resistance to intracellular pathogens. Since DC maturation is critical in determining the resulting immune response to antigenic stimuli, abnormal DC maturation could lead to dysfunctional immunity and disease. Examples of attenuated DC maturation have been reported in neoplastic and infectious disease processes. This proposal hypothesizes that the anergy in sarcoidosis is due to altered DC maturation. This hypothesis is supported by evidence in sarcoidosis for high plasma levels of IL-10 and vitamin D3, both )otential suppressors of DC maturation. This proposal outlines an approach to characterizing circulating blood DC subsets in normal volunteers and individuals with sarcoidosis, using flow cytometry phenotyping of whole blood DCs and magnetic column isolation and purification of these DCs to determine their effect on allogeneic T cell responses. Dendritic cell function will be correlated with in vivo cellular immune function as determined by PPD/anergy skin test panel. Associating altered DC maturation with T cell dysfunction in sarcoidosis would provide the basis for novel approaches in sarcoidosis therapies, including applying new DC-activating agents currently under development for the oncology and infectious disease fields.

描述（由申请人提供）： 结节病是一种病因不明的疾病，其特征是持续性肉芽肿并损害周围组织。尽管存在局灶性炎症，结节病患者经常对常见的皮肤反应物部分或完全无反应性，沿着其他全身细胞免疫抑制的证据。有证据表明，树突状细胞（DC），细胞免疫的关键调节器，可能有助于结节病的无能。DC在摄取和呈递抗原后诱导的T细胞应答的类型取决于DC亚群和成熟阶段。成熟DC主要诱导对效应T细胞应答、巨噬细胞活化和迟发型超敏反应至关重要的Th 1型应答。然而，任一亚群的未成熟DC可诱导T细胞无反应性，导致T细胞应答受损和对细胞内病原体的抗性降低。由于DC成熟在决定对抗原刺激的免疫应答中至关重要，异常的DC成熟可能导致免疫功能障碍和疾病。在肿瘤和感染性疾病过程中已经报道了减弱的DC成熟的实例。这一提议假设结节病的无反应性是由于DC成熟的改变。这一假说得到了结节病中高血浆水平IL-10和维生素D3（两者都是DC成熟的潜在抑制因子）的证据的支持。该提案概述了一种方法来表征正常志愿者和结节病患者的循环血DC亚群，使用全血DC的流式细胞术表型分析和这些DC的磁柱分离和纯化，以确定其对同种异体T细胞应答的影响。树突状细胞功能将与体内细胞免疫功能相关，如通过PPD/无反应性皮肤测试面板所确定的。将改变的DC成熟与结节病中的T细胞功能障碍相关联将为结节病治疗的新方法提供基础，包括应用目前正在开发的用于肿瘤学和感染性疾病领域的新DC活化剂。