Department of Neurology, Methodist Neurological Institute, Suite ST-802, 6560 Fannin Street, Houston, TX 77030, USA.
Brain. 2011 May;134(Pt 5):1293-314. doi: 10.1093/brain/awr074.
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.
肌萎缩侧索硬化症是一种无法治愈的进行性成人神经退行性疾病。在肌萎缩侧索硬化症的小鼠模型中，CD4+T 淋巴细胞和野生型小胶质细胞增强了保护性炎症反应，并在疾病进展中发挥主要作用。使用该模型，我们证明内源性 T 淋巴细胞，特别是调节性 T 淋巴细胞，在疾病进展缓慢的早期阶段增加，增加了白细胞介素 4 的表达和保护性 M2 小胶质细胞，并在疾病快速加速时减少，可能是通过调节性 T 淋巴细胞中 FoxP3 表达的丧失。在没有体外激活的情况下，将野生型 CD4+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并延长了生存期。将源自早期疾病阶段突变型 Cu2+/Zn2+超氧化物歧化酶小鼠的内源性调节性 T 淋巴细胞被动转移到这些肌萎缩侧索硬化症小鼠中，同样在没有体外激活的情况下，具有显著更强的免疫治疗作用，维持白细胞介素 4 水平和 M2 小胶质细胞，并延长疾病持续时间和延长生存期；使用突变型 Cu2+/Zn2+超氧化物歧化酶调节性 T 淋巴细胞，稳定疾病阶段延长了 88%。这种预期寿命延长的潜在机制可能是由突变型 Cu2+/Zn2+超氧化物歧化酶调节性 T 淋巴细胞的白细胞介素 4 分泌增加介导的，白细胞介素 4 直接抑制小胶质细胞的毒性；流式细胞术分析确定 CD4+/CD25+/FoxP3+T 淋巴细胞在同一细胞中共表达白细胞介素 4。这些观察结果扩展到肌萎缩侧索硬化症患者人群中，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 淋巴细胞的数量与疾病进展速度呈负相关。这些数据表明了一种细胞机制，其中内源性调节性 T 淋巴细胞具有免疫能力，并通过与小胶质细胞的相互作用积极促进神经保护。此外，这些数据表明免疫治疗干预必须在疾病的早期开始，因为免疫功能障碍发生在后期。因此，累积的小鼠和人类肌萎缩侧索硬化症数据表明，在疾病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，并减缓疾病进展速度，使患者更长时间保持稳定。
