GM-CSF THERAPY FOR ALVEOLAR PROTEINOSIS

GM-CSF 治疗肺泡蛋白沉积症

• 批准号: 6649259
• 负责人: Mary Jane Thomassen
• 金额: $ 34.43万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 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 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649259
• 关键词: B lymphocyte; antibody formation; autoantibody; clinical research; clinical trials; colony stimulating factor; epitope mapping; genetic polymorphism; human subject; human therapy evaluation; immunoconjugates; immunotherapy; interleukin 10; lymphocyte proliferation; nucleic acid sequence; patient oriented research; 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《调查者摘要》)：肺泡 蛋白沉着症(PAP)是一种非常罕见的肺部疾病，其特征是积聚 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)缺陷小鼠出现PAP样综合征 被外源性GM-CSF纠正，提示GM-CSF在正常人群中起着关键作用 肺内稳态与肺表面活性物质的清除。外源性给药 GM-CSF改善部分PAP患者的肺部疾病，提供支持 研究GM-CSF在人PAP中的作用。PAP来源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，表明没有固有缺陷 他们产生GM-CSF的能力或GM-CSF受体的能力。此外，所有PA 接受检测的患者在BAL和血清中都有GM-CSF抗体。 刺激抗体的多效性细胞因子--白介素10 也是一种有效的抑制肺泡细胞产生GM-CSF的药物 巨噬细胞。PAP患者支气管肺泡灌洗液中GM-CSF的检测较少 体液(BAL)，但IL-10水平高于健康对照组。IL-10 基因多态与某些自身免疫中IL-10的升高有关 疾病，但还没有出现在PAP中。单发PAP患者GM-CSF基因的多态性 患者已经被描述，尽管功能意义还没有被描述 学习。 根据这些数据，研究人员推测，在PAP中， GM-CSF的可用性因抗GM-CSF抗体和升高的 PAP中IL-10水平和这些事件可能与PAP的基因多态性相关 IL-10/GM-CSF基因。在一项开放标签II期临床试验的背景下 皮下注射GM-CSF治疗临床表现为 特发性或原发阵发性阵发性肺炎的恶化，申请人的 目的：(1)明确游离GM-CSF的临床意义， PAP患者血清中抗GM-CSF抗体及GM-CSF/抗体复合体的检测 对GM-CSF治疗的不同反应(应答者与无应答者)。(2) 通过研究(1)作用确定GM-CSF利用率降低的机制 利用GM-CSF识别的表位(S)在PAP中产生GM-CSF抗体的研究 抗体和(B)通过确定IL-10的细胞来源探讨IL-10在PAP中的作用 PAP中IL-10对GM-CSF产生的影响及IL-10对B细胞的影响 PAP患者的细胞增殖和抗体产生。(3)确定 PAP与IL-10/GM-CSF基因序列多态性的关系 分析。这项建议的长期目标是界定 抗GM-CSF抗体和IL-10在降低GM-CSF可用性中的作用 这在肺泡蛋白沉积症的病理生理学中起着关键作用。申请者 我觉得这些研究加上GM-CSF临床试验的数据将 为人类PAP的基本机制提供了新的见解。

项目成果

Elevated IL-10 inhibits GM-CSF synthesis in pulmonary alveolar proteinosis.

IL-10 升高会抑制肺泡蛋白沉积症中 GM-CSF 的合成。

• DOI: 10.1080/0891693031000152688
• 发表时间: 2003
• 期刊: Autoimmunity
• 影响因子: 3.5
• 作者: Thomassen,MaryJane;Raychaudhuri,Baisakhi;Bonfield,TraceyL;Malur,Anagha;Abraham,Susamma;Barna,BarbaraP;Kavuru,ManiS
• 通讯作者: Kavuru,ManiS

Surfactant blocks lipopolysaccharide signaling by inhibiting both mitogen-activated protein and IkappaB kinases in human alveolar macrophages.

表面活性剂通过抑制人肺泡巨噬细胞中的丝裂原激活蛋白和 IkappaB 激酶来阻断脂多糖信号传导。

• DOI: 10.1165/rcmb.2003-0263oc
• 发表时间: 2004
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Raychaudhuri,Baisakhi;Abraham,Susamma;Bonfield,TraceyL;Malur,Anagha;Deb,Amitabha;DiDonato,JosephA;Kavuru,ManiS;Thomassen,MaryJane
• 通讯作者: Thomassen,MaryJane