Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation
Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation
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DOI：
10.1002/ana.23784
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发表时间：
2013-03-01
影响因子：
11.2
通讯作者：
Bar-Or, Amit
中科院分区：
文献类型：
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作者：
Darlington, Peter J.;Touil, Tarik;Bar-Or, Amit
目的 明确接受消融化疗和自体造血干细胞移植 (HSCT) 治疗的侵袭性多发性硬化症 (MS) 患者的表型和重建 T 细胞功能反应的变化。方法 对参加加拿大 MS HSCT 研究的患者的疾病活动的临床和脑磁共振成像测量进行连续监测。通过流式细胞术测定免疫细胞亚群的重建动力学，而使用 T 细胞受体切除环分析以及 CD31+ 最近胸腺移出物 (RTE) 的流式细胞术测量来评估胸腺功能。进行功能测定以追踪中枢神经系统自身反应性抗原特异性 T 细胞反应，以及产生 Th1、Th17 或 Th1/17 T 细胞反应的相对能力。结果 在治疗后 2 年的免疫监测中，新的临床复发和新的局灶性炎症性脑损伤的完全消除与初始 T 细胞的持续减少有关，尽管在重建过程中胸腺功能和 RTE 的释放都得到了恢复。在所有研究的患者中，自身反应性 T 细胞的重新出现以及体内向多个髓磷脂靶标的扩增都是显而易见的。重建的髓磷脂特异性 T 细胞表现出与预消融髓磷脂反应性 T 细胞相同的 Th1 和 Th2 反应。相比之下，治疗后 T 细胞库表现出 Th17 反应能力显着下降。解释 我们的结果表明，Th17 和 Th1/17 反应的减弱，而不是 Th1 反应，与化疗消融和 HSCT 后侵袭性 MS 患者队列中观察到的新复发疾病活动的消除特别相关。安神经学 2013；73:341354
Objective To define changes in phenotype and functional responses of reconstituting T cells in patients with aggressive multiple sclerosis (MS) treated with ablative chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). Methods Clinical and brain magnetic resonance imaging measures of disease activity were monitored serially in patients participating in the Canadian MS HSCT Study. Reconstitution kinetics of immune-cell subsets were determined by flow cytometry, whereas thymic function was assessed using T-cell receptor excision circle analyses as well as flow cytometry measurements of CD31+ recent thymic emigrants (RTEs). Functional assays were performed to track central nervous systemautoreactive antigen-specific T-cell responses, and the relative capacity to generate Th1, Th17, or Th1/17 T-cell responses. Results Complete abrogation of new clinical relapses and new focal inflammatory brain lesions throughout the 2 years of immune monitoring following treatment was associated with sustained decrease in naive T cells, in spite of restoration of both thymic function and release of RTEs during reconstitution. Re-emergence as well as in vivo expansion of autoreactive T cells to multiple myelin targets was evident in all patients studied. The reconstituted myelin-specific T cells exhibited the same Th1 and Th2 responses as preablation myelin-reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses. Interpretation Our results indicate that diminished Th17 and Th1/17 responses, rather than Th1 responses, are particularly relevant to the abrogation of new relapsing disease activity observed in this cohort of patients with aggressive MS following chemoablation and HSCT. ANN NEUROL 2013;73:341354