Development of a clinical method to assess disease severity and treatment effect in idiopathic pulmonary alveolar proteinosis

开发评估特发性肺泡蛋白沉积症疾病严重程度和治疗效果的临床方法

• 批准号: 13671565
• 负责人: YAMADA Yoshitsugu
• 金额: $ 2.43万
• 依托单位: Yokohama City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671565/
• 关键词: autoantibody; GM-CSF; idiopathic pulmonary alveolar proteinosis; epitope mapping; autoantibody titer; neutralizing activity; binding avidity and specificity; biochemical parameter; 特発性肺胞蛋白症(iPAP); 抗GM-CSF自己抗体; 皮下注療法; 吸入療法; 特発性肺胞蛋白症; 顆粒球マクロファー

Autoantibodies against granulocyte-marcophage colony-stimulating factor (GM-CSF) are consistently and specifically detected in the serum and bronchoalveolar lavage fluid (BALF) in the patients with idiopathic pulmonary alveolar proteinosis (iPAP). The concentration of the autoantibody is 81.9 (median, range 4.7-686.3) μg/ml in the serum and 1.15 (0.09-5.4) μg/ml in the BALF.Autoantibodies against GMCSF have very high neutralizing activity and binding avidity, binding specificity. They recognize GMCSF superstructure. In iPAP patients, the autoantibodies against GM-CSF is proved to have enough capability to abrogate GM-CSF bioactivity in the lung. These results are published in the American Journal of Hematology.Significant correlations are observed between those parameters which indicate disease severity (i.e. PaO2, A-aDO2, and DLCO) and serum biochemical parameters (i.e. CEA, KL-6, SP-A). However, serum and BALF concentrationsof the autoantibody and neutralizing activity of the autoantibody purified from the serum have no correlation with disease severity.In 2 of 4 patients, the values of GM-CSF neutralizing activity in the serum paralleled the disease severity. This parameter has the possibility to be highly disease specific and minimum-invasive parameters for estimating disease severity of iPAP.

在特发性肺泡蛋白沉积症（iPAP）患者的血清和支气管肺泡灌洗液（BALF）中一致且特异性地检测到抗粒细胞-噬菌体集落刺激因子（GM-CSF）的自身抗体。血清中自身抗体浓度为81.9（中位数，范围4.7 ~ 686.3）μg/ml， BALF中抗体浓度为1.15 (0.09 ~ 5.4)μg/ml。抗GMCSF自身抗体具有很高的中和活性和结合亲和度、结合特异性。他们认出了GMCSF的上层建筑。在iPAP患者中，抗GM-CSF的自身抗体被证明有足够的能力消除GM-CSF在肺中的生物活性。这些结果发表在《美国血液学杂志》上。表明疾病严重程度的参数（如PaO2、A-aDO2和DLCO）与血清生化参数（如CEA、KL-6、SP-A）之间存在显著相关性。然而，血清中自身抗体和BALF浓度以及从血清中纯化的自身抗体的中和活性与疾病严重程度无关。在4例患者中的2例中，血清中GM-CSF中和活性值与疾病严重程度平行。该参数有可能成为估计iPAP疾病严重程度的高度疾病特异性和最小侵入性参数。

项目成果

内田 寛治: "サイトカインの自己抗体が起こす病体-特発性肺胞蛋白症-"最新医学. 56・6. 1254-1258 (2001)

Hiroharu Uchida：“由细胞因子自身抗体引起的疾病 - 特发性肺泡蛋白沉积症”现代医学 56・6（2001）。

Tranpnell B, whitsett J, Nakata K: "Pulmonary Alveolar Proteinosis ; Mechanism of Disease"New England Journal of Medicine. 349. 2528-2540 (2003)

Tranpnell B、whitsett J、Nakata K：“肺泡蛋白沉积症；疾病机制”新英格兰医学杂志。

Seymour JF, Doyle IR, Nakata K, Presneil U, AR Dunn: "Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and LDH to pulmonary parameters and response to GM-CSF therapy in patientsn with idiopathic alveolar proteinosis"T

Seymour JF、Doyle IR、Nakata K、Presneil U、AR Dunn：“特发性肺泡患者中抗 GM-CSF 抗体浓度、表面活性蛋白 A 和 B 水平以及 LDH 与肺部参数和对 GM-CSF 治疗反应的关系

Schoch OD, Schanz U, Koller M, Nakata K, Seymour JF, Russi EW, Boehler A: "Bronchoalveolar lavage findings in a patient with pulmonary alveolar proteinosis successfully treated with GM-CSF"Thorax. 57. 277-280 (2002)

Schoch OD、Schanz U、Koller M、Nakata K、Seymour JF、Russi EW、Boehler A：“用 GM-CSF 成功治疗肺泡蛋白沉积症患者的支气管肺泡灌洗结果”Thorax。

Miyashita T: "Spectral analyses of electroencephalography and heart rate variability during sleep in normal subjects. Autonomic Neuroscience"Basic and Clinical. 103. 114-120 (2003)

Miyashita T：“正常受试者睡眠期间脑电图和心率变异性的频谱分析。自主神经科学”基础和临床。