The role of Wilms' tumor gene peptide-specific cytotoxic T lymphocytes in immunologic selection of a paroxysmal nocturnal hemoglobinuria clone
The role of Wilms' tumor gene peptide-specific cytotoxic T lymphocytes in immunologic selection of a paroxysmal nocturnal hemoglobinuria clone
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DOI：
10.1016/j.exphem.2007.01.045
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发表时间：
2007-04-01
影响因子：
2.6
通讯作者：
Maruyama, Yukio
中科院分区：
文献类型：
--
作者：
Ikeda, Kazuhiko;Shichishima, Tsutomu;Maruyama, Yukio
Objective.阐明具有肾母细胞瘤基因（WT 1）的阵发性睡眠性血红蛋白尿症（PNH）克隆的扩增机制。在具有HLA-A*2402等位基因的PNH患者中，外周血（PB）WT 1肽特异性和HLA-A*2402限制性CD 8（+）细胞和WT 1肽刺激的产生干扰素γ的单核细胞（MNC）的频率，WT 1肽特异性和HLA-A*2402限制性细胞毒性T淋巴细胞（CTL）克隆（TAK-1）细胞对骨髓（BM）MNC的细胞毒性，与TAK-1细胞共孵育后，观察CD 34（+）细胞集落形成单位粒-巨噬细胞集落形成和活CD 34（+）细胞CD 59表达的变化。5例PNH患者PB WT 1肽特异性和HLA-A*2402限制性CD 8+细胞（p < 0.005）和WT 1肽刺激的产生干扰素γ的MNC（p < 0.02）的频率显著高于8例健康志愿者（HV）。在5例PNH患者或3例HV中，TAK-1细胞分别在不存在和存在WT 1肽或仅存在WT 1肽的情况下以HLA限制性方式显著杀死BMMNC并抑制CD 34（+）CD 59（+）和/或CD 34（+）CD 59（-）细胞的集落形成。与TAK-1细胞共孵育后，5例PNH患者CD 34（+）CD 59（-）细胞集落形成率明显低于CD 34（+）CD 59（+）细胞集落形成率5例PNH患者的CD 34（+）CD 59（-）细胞比例在缺乏CD 34（+）CD 59（-）细胞的情况下显著增加（P < 0.002（p < 0.01）和WT 1肽的存在（p < 0.01）。WTI肽特异性和HLA限制性CTL可能在免疫选择期间PNH克隆的扩增和/或在PNH中通过干扰素-γ发生BM失败中发挥重要作用。(c)2007年国际实验血液学学会。爱思唯尔公司出版
Objective. To clarify an expansion mechanism of a paroxysmal nocturnal hemoglobinuria (PNH) clone with the Wilms' tumor gene (WT1).Materials and Methods. In PNH patients with the HLA-A*2402 allele, frequencies of peripheral blood (PB) WT1 peptide-specific and HLA-A*2402-restrieted CD8(+) cells and WT1 peptide-stimulated interferon-gamma-producing mononuclear cells (MNCs), cytotoxicity of WT1 peptide-specific and HLA-A*2402-restricted cytotoxic T lymphocyte (CTL) clone (TAK-1) cells on bone marrow (BM) MNCs, and after co-incubation with TAK-1 cells, changes in colony-forming unit granulocyte-macrophage colony formation of CD34(+) cells and in CD59 expression in viable CD34(+) cells were investigated.Results. The frequencies of PB WT1 peptide-specific and HLA-A*2402-restricted CD8+ cells (p < 0.005) and WT1 peptide-stimulated interferon-gamma-producing MNCs (p < 0.02) were significantly higher in 5 PNH patients than 8 healthy volunteers (HV). In 5 PNH patients or 3 HV, TAK-1 cells significantly killed BMMNCs and suppressed colony formations of CD34(+)CD59(+) and/or CD34(+)CD59(-) cells in the absence and presence of a WT1 peptide or only in the presence of the peptide, respectively, in an HLA-restricted manner. After coincubation with TAK-1 cells, reduction rates of colony formation of CD34(+)CD59(-) cells were significantly less than those of CD34(+)CD59(+) cells in 5 PNH patients (P < 0.002) and proportions of viable CD34(+)CD59(-) cells from 5 PNH patients significantly increased in the absence (p < 0.01) and presence (p < 0.01) of a WT1 peptide in an HLA-restricted manner.Conclusion. WTI peptide-specific and HLA-restricted CTLs may play an important role in expansion of a PNH clone during immunologic selection and/or in the occurrence of BM failure via interferon-gamma in PNH. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.