Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis.
Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis.
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DOI：
10.1093/brain/awr074
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发表时间：
2011-05
期刊：
影响因子：
--
通讯作者：
Appel SH
中科院分区：
文献类型：
--
作者：
Beers DR;Henkel JS;Zhao W;Wang J;Huang A;Wen S;Liao B;Appel SH
肌萎缩侧索硬化症是一种无情的和毁灭性的成人发病的神经退行性疾病，没有已知的治疗。在患有肌萎缩侧索硬化症的小鼠中，CD 4 + T淋巴细胞和野生型小胶质细胞增强保护性炎症反应，并在疾病的病理进展中发挥主要作用。使用这个模型，我们证明内源性T淋巴细胞，更具体地说是调节性T淋巴细胞，在早期缓慢进展阶段增加，增加白细胞介素-4表达和保护性M2小胶质细胞，而当疾病迅速加速时，可能通过FoxP 3的丧失而减少调节性T淋巴细胞中的表达。在没有体外激活的情况下，将野生型CD 4 + T淋巴细胞被动转移到缺乏功能性T淋巴细胞的肌萎缩侧索硬化症小鼠中，延长了疾病持续时间和生存期。内源性调节性T淋巴细胞从早期疾病阶段突变型Cu 2 +/Zn 2+超氧化物歧化酶小鼠被动转移到这些肌萎缩侧索硬化症小鼠中，同样没有离体活化，实质上更免疫维持白细胞介素-4水平和M2小胶质细胞，并导致延长的疾病持续时间和延长的存活;使用突变的Cu 2 +/Zn 2+超氧化物歧化酶调节性T淋巴细胞，稳定疾病期延长了88%。一个潜在的机制，这种增强的预期寿命可能是介导的增强分泌的白细胞介素-4从突变的Cu 2 +/Zn 2+超氧化物歧化酶调节T淋巴细胞，直接抑制小胶质细胞的毒性特性;流式细胞仪分析确定，CD 4 +/CD 25 +/FoxP 3 + T淋巴细胞共表达白细胞介素-4在同一个细胞。这些观察结果扩展到肌萎缩侧索硬化患者人群，其中疾病进展更快的患者调节性T淋巴细胞数量减少;调节性T淋巴细胞数量与疾病进展率呈负相关。这些数据表明内源性调节性T淋巴细胞具有免疫活性，并通过与小胶质细胞的相互作用积极促进神经保护的细胞机制。此外，这些数据表明，免疫干预必须在致病过程的早期开始，因为免疫功能障碍发生在后期。因此，小鼠和人类肌萎缩侧索硬化症的累积数据表明，在疾病过程的早期阶段增加肌萎缩侧索硬化症患者的调节性T淋巴细胞水平可能具有治疗价值，并减缓疾病进展的速度，使患者稳定更长的时间。
Amyotrophic lateral sclerosis is a relentless and devastating adult-onset neurodegenerative disease with no known cure. In mice with amyotrophic lateral sclerosis, CD4+ T lymphocytes and wild-type microglia potentiate protective inflammatory responses and play a principal role in disease pathoprogression. Using this model, we demonstrate that endogenous T lymphocytes, and more specifically regulatory T lymphocytes, are increased at early slowly progressing stages, augmenting interleukin-4 expression and protective M2 microglia, and are decreased when the disease rapidly accelerates, possibly through the loss of FoxP3 expression in the regulatory T lymphocytes. Without ex vivo activation, the passive transfer of wild-type CD4+ T lymphocytes into amyotrophic lateral sclerosis mice lacking functional T lymphocytes lengthened disease duration and prolonged survival. The passive transfer of endogenous regulatory T lymphocytes from early disease stage mutant Cu2+/Zn2+ superoxide dismutase mice into these amyotrophic lateral sclerosis mice, again without ex vivo activation, were substantially more immunotherapeutic sustaining interleukin-4 levels and M2 microglia, and resulting in lengthened disease duration and prolonged survival; the stable disease phase was extended by 88% using mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes. A potential mechanism for this enhanced life expectancy may be mediated by the augmented secretion of interleukin-4 from mutant Cu2+/Zn2+ superoxide dismutase regulatory T lymphocytes that directly suppressed the toxic properties of microglia; flow cytometric analyses determined that CD4+/CD25+/FoxP3+ T lymphocytes co-expressed interleukin-4 in the same cell. These observations were extended into the amyotrophic lateral sclerosis patient population where patients with more rapidly progressing disease had decreased numbers of regulatory T lymphocytes; the numbers of regulatory T lymphocytes were inversely correlated with disease progression rates. These data suggest a cellular mechanism whereby endogenous regulatory T lymphocytes are immunocompetent and actively contribute to neuroprotection through their interactions with microglia. Furthermore, these data suggest that immunotherapeutic interventions must begin early in the pathogenic process since immune dysfunction occurs at later stages. Thus, the cumulative mouse and human amyotrophic lateral sclerosis data suggest that increasing the levels of regulatory T lymphocytes in patients with amyotrophic lateral sclerosis at early stages in the disease process may be of therapeutic value, and slow the rate of disease progression and stabilize patients for longer periods of time.
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影响因子：
64.8
作者：
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通讯作者：
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