Mitoxantrone induces cell death in peripheral blood leucocytes of multiple sclerosis patients
Mitoxantrone induces cell death in peripheral blood leucocytes of multiple sclerosis patients
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DOI：
10.1111/j.1365-2249.2005.02653.x
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发表时间：
2005-01-01
影响因子：
4.6
通讯作者：
Gold, R
中科院分区：
文献类型：
--
作者：
Chan, A;Weilbach, FX;Gold, R
米托蒽醌（MX）是一种细胞毒性药物，已证实对活动性多发性硬化（MS）有临床疗效。在这项离体研究中，我们研究了MX对MS患者外周血白细胞（PBL）的免疫学作用。46例活动性MS患者（平均年龄42岁，女性：男性1.4：1）在MX输注前和输注后1小时立即分离PBL。分离的PBL用植物血凝素（PHA）、T细胞受体刺激单克隆抗体（MoAb）X35刺激或单独保存在培养基中培养。通过[H-3]-胸苷掺入来测量增殖。PBL亚群中的MX摄取和细胞死亡通过流式细胞术使用针对分化簇（CD）表面抗原、膜联蛋白V（AnnV）和碘化丙啶（PI）的抗体进行分析。MX被迅速掺入PBL。在体内暴露仅1小时后，MX降低未刺激和刺激PBL的增殖反应（PHA：-17%，MoAb X35：-13%）。MX暴露的PBL显示AnnV（+）/PI+细胞增加（未刺激：12%，PHA：15%），输注后2周更明显。初治MX治疗患者与长期MX治疗患者之间未观察到差异。在T细胞受体刺激的PBL中，细胞死亡优先在CD 19阳性B细胞中诱导，在较小程度上在CD 8阳性T细胞中诱导。MX被迅速纳入MS患者的循环PBL中，并诱导明显的增殖反应抑制。这种抑制似乎至少部分是通过诱导晚期凋亡/坏死细胞死亡介导的，B细胞具有优先易感性。
Mitoxantrone (MX) is a cytotoxic drug with proven clinical efficacy in active multiple sclerosis (MS). In this ex vivo study we investigated the immunological effects of MX on peripheral blood leucocytes (PBL) from MS patients. PBL were isolated from 46 patients with active MS (mean age 42 years, female : male 1.4 : 1) before and immediately after 1 h MX infusion. Isolated PBL were cultured and stimulated with phytohaemagglutinin (PHA), T cell receptor stimulating monoclonal antibody (MoAb) X35 or kept in culture medium alone. Proliferation was measured by [H-3]-thymidine incorporation. MX-uptake and cell death in PBL subpopulations was analysed by flow cytometry using antibodies against cluster of differentiation (CD)-surface antigens, annexin V (AnnV) and propidium iodide (PI). MX was incorporated rapidly into PBL. After only a 1-h in vivo exposure, MX reduced proliferative responses in unstimulated and stimulated PBL (PHA: - 17%, MoAb X35: - 13%). MX-exposed PBL showed an increase of AnnV(+)/PI+ cells (unstimulated: 12%, PHA: 15%), which was even more pronounced 2 weeks after infusion. No difference was observed between de novo MX-treated patients and those on long-term MX treatment. In T cell receptor stimulated PBL, cell death was induced preferentially in CD19-positive B cells and to a lesser extent in CD8-positive T cells. MX is incorporated rapidly in circulating PBL of MS patients and induces a pronounced suppression of proliferative responses. This suppression appears to be mediated at least partly by the induction of late apoptotic/necrotic cell death with a preferential susceptibility of B cells.