GM-CSF THERAPY FOR ALVEOLAR PROTEINOSIS

GM-CSF 治疗肺泡蛋白沉积症

• 批准号: 6528019
• 负责人: Mary Jane Thomassen
• 金额: $ 32.1万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528019
• 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：（改编自研究者摘要）：肺泡 蛋白质沉积症（PAP）是一种非常罕见的肺部疾病，其特征是 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）缺陷型小鼠发生PAP样综合征， 通过外源性GM-CSF校正，表明GM-CSF在正常人中的关键作用。 肺内环境稳定和表面活性剂的清除。给予外源性 GM-CSF改善PAP患者亚组的肺部疾病，提供支持 GM-CSF在人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，表明无内在缺陷 产生GM-CSF的能力或GM-CSF受体。此外，所有PA 检测的患者在BAL和血清中具有抗GM-CSF的抗体。 白细胞介素-10（IL-10）是一种多效性细胞因子， 产生，也是从肺泡产生GM-CSF的有效抑制剂 巨噬细胞PAP患者支气管肺泡灌洗液中GM-CSF的检出率较低 液体（BAL），但IL-10水平高于健康对照。IL-10 在某些自身免疫性疾病中， 疾病，但还没有在PAP。单一PAP患者GM-CSF基因多态性的研究 患者已被描述，虽然功能的意义还没有 研究了 基于这些数据，研究人员假设，在PAP中， 抗GM-CSF抗体降低了GM-CSF的可用性， IL-10水平和PAP中的这些事件可能与 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 对于特发性或原发性PAP的恶化，申请人提出 目的：（1）明确游离GM-CSF的临床意义， PAP患者抗GM-CSF抗体和GM-CSF/抗体复合物的检测 对GM-CSF治疗的不同应答（应答者与无应答者）。（二） 通过研究确定GM-CSF可用性降低的机制（1）作用 通过定位GM-CSF识别的表位， 抗体和（B）通过确定IL-10的细胞来源确定IL-10在PAP中的作用 在PAP中，IL-10对GM-CSF产生的影响和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基因多态性的相关性 分析.这项建议的长期目标是界定 抗GM-CSF抗体和IL-10降低GM-CSF的可用性， 其在肺泡蛋白沉积症的病理生理学中是关键的。申请人 我认为这些研究加上GM-CSF临床试验的数据， 为人类PAP的基本机制提供了新的见解。