GM-CSF THERAPY FOR ALVEOLAR PROTEINOSIS

GM-CSF 治疗肺泡蛋白沉积症

• 批准号: 6313660
• 负责人: Mary Jane Thomassen
• 金额: $ 32.82万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6313660
• 关键词: B lymphocyte; antibody formation; autoantibody; clinical research; colony stimulating factor; epitope mapping; genetic polymorphism; human subject; human therapy evaluation; immunoconjugates; immunotherapy; interleukin 10; lymphocyte proliferation; nucleic acid sequence; pulmonary alveolar proteinosis

DESCRIPTION:(Adapted from Investigator's abstract): Pulmonary alveolar proteinosis (PAP) is a very rare lung disease characterized by the accumulation of surfactant material within the alveoli. Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) deficient mice develop a PAP like syndrome which is corrected by exogenous GM-CSF, suggesting a pivotal role for GM-CSF in normal lung homeostasis and clearance of surfactant. Administration of exogenous GM-CSF ameliorates lung disease in a subset of PAP patients, providing support for GM-CSF role in human PAP. Monocytes and alveolar macrophages from PAP patients produce GM-CSF and respond to GM-CSF, indicating no intrinsic defects in their ability to produce GM-CSF or in the GM-CSF receptor. Further, all PA patients tested have antibodies against GM-CSF in the BAL and serum. Iinterleukin-10 (IL-10), a pleiotropic cytokine which stimulates antibody production, is also a potent inhibitor of GM-CSF production from alveolar macrophages. PAP patients have less detectable GM-CSF in bronchoalveolar lavage fluids (BAL) but higher levels of IL-10 than healthy controls. IL-10 polymorphisms have been associated with increased IL-10 in some autoimmune diseases, but not yet in PAP. A polymorphism in the GM-CSF gene of a single PAP patient has been described, although the functional significance has not been studied. Based on these data, the investigators hypothesize that in PAP, the availability of GM-CSF is decreased by anti-GM-CSF antibodies and by elevated levels of IL-10 and these events in PAP may be associated with polymorphisms in the IL-10/GM-CSF genes. In the context of an open-label Phase II clinical trail of treatment with subcutaneous GM-CSF for patients presenting with exacerbations of idiopathic or primary PAP, the applicant's propose the following aims: (1) Define the clinical significance of free GM-CSF, anti-GM-CSF antibodies and GM-CSF/antibody complexes in PAP patients with differential response to GM-CSF therapy (responders versus non-responders). (2) Determine mechanisms of decreased GM-CSF availability by investigating (1) Role of GM-CSF antibody production in PAP by mapping epitope(s) recognized by GM-CSF antibody and (b) Role of IL-10 in PAP by determining cellular source of IL-10 in PAP, the effect of IL-10 on GM-CSF production and the effect of IL-10 on B cell proliferation and antibody production of PAP patients. (3) Determine the association of PAP with polymorphisms in the IL-10/GM-CSF genes by sequence analysis. The long-term objective of this proposal is to delineate the role of anti-GM-CSF antibodies and IL-10 in decreasing the availability of GM-CSF, which is pivotal in the pathophysiology of alveolar proteinosis. The applicants feel that these studies coupled with data from the GM-CSF clinical trial will provide novel insights into the basic mechanisms underlying human PAP.

描述：（改编自研究者的摘要）：肺泡 蛋白沉积症（PAP）是一种非常罕见的肺部疾病，其特征是蛋白沉积 肺泡内的表面活性物质。粒细胞巨噬细胞集落 刺激因子 (GM-CSF) 缺陷小鼠会出现类似 PAP 的综合征 外源性 GM-CSF 可以纠正这一现象，表明 GM-CSF 在正常情况下发挥着关键作用。 肺稳态和表面活性剂的清除。外源性给药 GM-CSF 可改善部分 PAP 患者的肺部疾病，提供支持 GM-CSF 在人类 PAP 中的作用。 PAP 中的单核细胞和肺泡巨噬细胞 患者产生 GM-CSF 并对 GM-CSF 有反应，表明没有内在缺陷 其产生 GM-CSF 或 GM-CSF 受体的能力。此外，所有 PA 接受测试的患者的 BAL 和血清中含有针对 GM-CSF 的抗体。 Iinterleukin-10 (IL-10)，一种刺激抗体的多效细胞因子 产生，也是肺泡产生 GM-CSF 的有效抑制剂 巨噬细胞。 PAP 患者支气管肺泡灌洗液中检测不到的 GM-CSF 体液 (BAL)，但 IL-10 水平高于健康对照。白细胞介素10 多态性与某些自身免疫性疾病中 IL-10 的增加有关 疾病，但尚未出现在 PAP 中。单个 PAP 的 GM-CSF 基因多态性 已对患者进行了描述，但其功能意义尚未明确 研究过。 根据这些数据，研究人员推测，在 PAP 中， 抗 GM-CSF 抗体和升高的 GM-CSF 可用性会降低 PAP 中 IL-10 水平和这些事件可能与 IL-10/GM-CSF 基因。在开放标签 II 期临床试验的背景下 皮下注射 GM-CSF 治疗患者的效果 特发性或原发性 PAP 恶化，申请人建议 以下目标： (1) 定义游离 GM-CSF 的临床意义， PAP 患者中的抗 GM-CSF 抗体和 GM-CSF/抗体复合物 对 GM-CSF 治疗的不同反应（有反应者与无反应者）。 (2) 通过调查 (1) 作用确定 GM-CSF 可用性降低的机制 通过绘制 GM-CSF 识别的表位来分析 PAP 中 GM-CSF 抗体的产生 (b) 通过确定 IL-10 的细胞来源来了解 IL-10 在 PAP 中的作用 在 PAP 中，IL-10 对 GM-CSF 产生的影响以及 IL-10 对 B 的影响 PAP 患者的细胞增殖和抗体产生。 (3) 确定 PAP 与 IL-10/GM-CSF 基因多态性（按序列）的关联 分析。该提案的长期目标是界定 抗GM-CSF抗体和IL-10降低GM-CSF的可用性， 这在肺泡蛋白沉积症的病理生理学中至关重要。申请人 认为这些研究与 GM-CSF 临床试验的数据相结合将 为人类 PAP 的基本机制提供了新的见解。