Identification of autoantigens in autoimmune aplastic anemia

自身免疫性再生障碍性贫血中自身抗原的鉴定

• 批准号: 11670987
• 负责人: NAKAO Shinji
• 金额: $ 2.56万
• 依托单位: kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670987/
• 关键词: Aplastic anemia; Cytotoxic T cell; paroxysmal nectumal hemoglabinuric; GPI-anchored membrane protein; ペプチドライブラリー; SEREX; αグロビン; ribosomal protein

Idiopathic aplastic anemia (AA) is considered to be a kind of autoimmune disease caused by a T-cell attack against hematopoi*stem cells although little is know about target antigens of the immune attack. We isolated a CD4+ T-cell clone termed ZN1 from the bone marrow of a patient with immume-mediated aplastic anemia. Using the combinatorial random peptide library, we attempted to identify a candidate epitope of ZN1. Several 11-mer peptides were found to stimulate proliferation to the T-cell clone, however, none of them proved to be related to hematopoietic cells. Since a CLIP-replacement peptide library has been shown to be useful in identify an epitope of CD4+ T-cell clone, we are planning to test this library. On the other hand, there has been no evidence that cytotoxic T cells (CTIs) indeed participate in the attack of hematopoietic stem cells in AA.We previously demonstrated that hematopoietic cells need to express glycosylphosphatidylinositol (GPI)-anchored membrane proteins such … More as CD59 and CD58, to be efficiently killed by a CTL, NT4.2, that was isolated from the bone marrow of an immune-mediated AA patient. To estimate how frequent CTLs are involved in the development of bone marrow failure, we examined peripheral blood of newly diagnosed AA patients for the presence of granulocytes deficient of GPI-anchored proteins using a sensitive flow cytometry. A significant increase in the percentage of CD55-CD59- (PNH) in CD11b+ granulocytes (_0.003%) was observed in 31 of 35 patients (88.6%). When peripheral blood of 19 patients showing increased PNH granulocytes was studied again at 6 months after antithymocyte globalin therapy, the percentage of PNH granulocytes had decreased to 0.01-90% of the pretreatment values in 15 of 18 recovering patients. These findings suggest that the increased percentage of PNH granulocytes reflects the presence of CTL attack against normal hematopoietic stem cells and that such immune mechanisms may be operative in approximately 90% of AA patients. Less

特发性再生障碍性贫血（Idiopathic aplastic anemia，AA）被认为是一种由T细胞攻击造血干细胞而引起的自身免疫性疾病，但对这种免疫攻击的靶抗原知之甚少。我们从免疫介导的再生障碍性贫血患者的骨髓中分离出一个CD 4 + T细胞克隆，命名为ZN 1。利用组合随机肽库，我们尝试鉴定ZN 1的候选表位。几个11-mer肽被发现刺激增殖的T细胞克隆，但是，没有一个被证明是与造血细胞。由于CLIP置换肽库已被证明可用于鉴定CD 4 + T细胞克隆的表位，因此我们计划测试该文库。另一方面，没有证据表明细胞毒性T细胞（CTIs）确实参与了AA中造血干细胞的攻击。 ...更多信息 如CD 59和CD 58，被从免疫介导的AA患者的骨髓中分离的CTL NT 4.2有效地杀死。为了估计CTL参与骨髓衰竭发展的频率，我们使用灵敏的流式细胞术检查了新诊断的AA患者的外周血中缺乏GPI锚定蛋白的粒细胞的存在。35例患者中有31例（88.6%）观察到CD 11b+粒细胞中CD 55-CD 59-（PNH）百分比显著增加（_0.003%）。在抗胸腺细胞globalin治疗后6个月再次研究19例PNH粒细胞增加的患者的外周血时，18例恢复患者中有15例的PNH粒细胞百分比下降至治疗前值的0.01-90%。这些研究结果表明，PNH粒细胞的百分比增加反映了CTL攻击正常造血干细胞的存在，这种免疫机制可能在大约90%的AA患者中起作用。少

项目成果

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中尾真二: "再生不良性貧血および不応性貧血における「NHクローンの意識」Annal Review血液"高久史磨,溝口秀昭,小宮山淳,坂田洋一,金倉譲 編,中外医学社. 6 (2001)

Shinji Nakao：“再生障碍性贫血和难治性贫血中的‘NH 克隆意识’”血液年鉴，Fumima Takaku、Hideaki Mizoguchi、Jun Komiyama、Yoichi Sakata、Joe Kanakura（编辑），Chugai Igakusha 6 (2001)。

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Zeng W等人：“免疫介导的再生障碍性贫血骨髓中T细胞库的表征：抗原驱动的T细胞反应参与环孢素依赖性再生障碍性贫血的证据”血液。

Wang H et al.: "Relative increase of granulocytes with a paroxysmal nocturnal haemoglobinuria phenotype in oplastic anaemia patients : the high prevalence at diagnosis"Eur J Haemaol. (in press). (2001)

Wang H 等人：“再生性贫血患者中具有阵发性睡眠性血红蛋白尿表型的粒细胞相对增加：诊断时的患病率很高”Eur J Haemaol。

Takami A,et al.: "High inducibility of heat shock protein 72(hsp72) in peripheral blood mononuclear cells of aplastic anaemia patients: a reliable marker of immune-mediated aplastic anemia responsive to cyclosporine therapy"Br J Haematol. 106・2. 377 (1999

Takami A 等人：“再生障碍性贫血患者外周血单核细胞中热休克蛋白 72 (hsp72) 的高诱导性：免疫介导的再生障碍性贫血对环孢素治疗有反应的可靠标志物”Br J Haematol 106・2。 377 (1999