A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy
A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy
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DOI：
10.1016/j.jcyt.2016.06.012
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发表时间：
2016-10-01
期刊：
影响因子：
4.5
通讯作者：
Rezvani, Katayoun
中科院分区：
文献类型：
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作者：
Alsuliman, Abdullah;Appel, Stanley H.;Rezvani, Katayoun
调节性T细胞(Tregs)在维持自身耐受和免疫动态平衡方面起着重要作用。Treg功能和/或频率的缺陷在多种疾病模型中都有报道。肌萎缩侧索硬化症(ALS)是一种累及上下运动神经元的进行性神经退行性疾病。令人信服的证据支持Tregs在这种疾病中的神经保护作用。事实上，ALS患者的快速进展与FoxP3表达和Treg频率的降低有关。因此，我们提出恢复Treg数量和功能的策略可能会减缓ALS的疾病进展。在这项研究中，我们开发了一种健壮的、符合GMP的程序来丰富和扩大ALS患者的Tregs。从这些患者中分离出的Tregs的表型与健康人的相似，但它们抑制T细胞效应功能的能力受到了损害。在GMP级抗CD3/CD28微球、白介素2和雷帕霉素的存在下，Tregs在体外扩增4周后，其数量增加了25~200倍，并恢复了免疫调节活性。总而言之，我们的数据促进和支持了在ALS患者中实施体外扩张和高度抑制的Tregs过继治疗的临床试验。
Regulatory T cells (Tregs) play a fundamental role in the maintenance of self-tolerance and immune homeostasis. Defects in Treg function and/or frequencies have been reported in multiple disease models. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Compelling evidence supports a neuroprotective role for Tregs in this disease. Indeed, rapid progression in ALS patients is associated with decreased FoxP3 expression and Treg frequencies. Thus, we propose that strategies to restore Treg number and function may slow disease progression in ALS. In this study, we developed a robust, Good Manufacturing Practice (GMP) compliant procedure to enrich and expand Tregs from ALS patients. Tregs isolated from these patients were phenotypically similar to those from healthy individuals but were impaired in their ability to suppress T-cell effector function. In vitro expansion of Tregs for 4 weeks in the presence of GMP-grade anti-CD3/CD28 beads, interleukin (IL)-2 and rapamcyin resulted in a 25- to 200-fold increase in their number and restored their immunoregulatory activity. Collectively, our data facilitate and support the implementation of clinical trials of adoptive therapy with ex vivo expanded and highly suppressive Tregs in patients with ALS.