Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis
Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis
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DOI：
10.1212/01.wnl.0000327668.43541.22
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发表时间：
2008-10-21
期刊：
影响因子：
9.9
通讯作者：
Popat, U.
中科院分区：
文献类型：
--
作者：
Appel, S. H.;Engelhardt, J. I.;Popat, U.
背景：肌萎缩侧索硬化症（ALS）是一种不可避免的进展性运动神经元疾病，伴有炎症标志物显着增加。这些炎症成分可以保护、伤害、或两者兼而有之。 目的：对散发性 ALS 患者进行同种异体造血干细胞移植（HSCT），以抑制神经炎症并改善中枢神经系统移植后的临床结果。 方法：6 名确诊 ALS 患者接受全身照射，然后输注来自人类白细胞抗原相同匹配的同胞供者的外周血 HSCT。每月评估疾病进展和生存率，并与匹配的历史数据库患者进行比较。通过免疫组织化学和定量逆转录酶聚合酶链反应对脑和脊髓的尸检样本进行检查。评估了脑和脊髓组织中供体来源的 DNA 的嵌合程度。结果：没有明显的临床益处。 4 名患者 100% 植入；对两名 100% 移植患者的尸检组织检查显示，在运动神经元病理部位有 16% 至 38% 的供体来源的 DNA，这可能与观察到的 CD68 或 CD1a 阳性细胞增加相对应。在几个未受影响的大脑区域中，既没有发现供体 DNA，也没有发现细胞数量增加。第三名最低限度移植的患者中枢神经系统既没有供体 DNA，也没有增加的浸润细胞。结论：这项研究表明，源自供体造血干细胞的外周细胞可以主要在运动神经元病理部位进入人类中枢神经系统，并作为免疫调节细胞移植。尽管未经修饰的造血干细胞并没有使这些散发性肌萎缩侧索硬化症患者受益，但此类细胞可能为未来的中枢神经系统基因治疗提供细胞载体。神经病学（R）2008； 71：1326-1334
Background: Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, harm, do neither, or do both.Objective: Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in patients with sporadic ALS to suppress neuroinflammation and improve clinical outcomes after CNS engraftment.Methods: Six patients with definite ALS received total body irradiation followed by peripheral blood HSCT infusion from human leukocyte antigen identically matched sibling donors. Disease progression and survival were assessed monthly and compared with matched historic database patients. Autopsy samples from brain and spinal cord were examined immunohistochemically and by quantitative reverse-transcriptase polymerase chain reaction. Donor-derived DNA in brain and spinal cord tissue was evaluated for the extent of chimerism.Results: No clinical benefits were evident. Four patients were 100% engrafted; postmortem tissue examination in two of the 100% engrafted patients demonstrated 16% to 38% donor-derived DNA at sites with motoneuron pathology, which may correspond to the observed increased CD68 or CD1a-positive cells. Neither donor DNA nor increased cell numbers were found in several unaffected brain regions. A third minimally engrafted patient had neither donor DNA nor increased infiltrating cells in the CNS.Conclusions: This study demonstrates that peripheral cells derived from donor hematopoietic stem cells can enter the human CNS primarily at sites of motoneuron pathology and engraft as immunomodulatory cells. Although unmodified hematopoietic stem cells did not benefit these sporadic amyotrophic lateral sclerosis patients, such cells may provide a cellular vehicle for future CNS gene therapy. Neurology (R) 2008; 71: 1326-1334