Valerie E Teschner, Ann-Katrin Fleck, Carolin Walter, Anna-Sophie Schwarze, Melanie Eschborn, Timo Wirth, Olga V Steinberg, Andreas Schulte-Mecklenbeck, I-Na Lu, Marisol Herrera-Rivero, Claudia Janoschka, Jan D Lünemann, Nicholas Schwab, Gerd Meyer Zu Hörste, Julian Varghese, Catharina C Gross, Refik Pul, Christoph Kleinschnitz, Simone Mader, Edgar Meinl, Monika Stoll, Heinz Wiendl, Luisa Klotz
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引用次数: 0
Abstract
Background: Cladribine is a highly effective immunotherapy that is applied in two short-term courses over 2 years and reduces relapse rate and disease progression in patients with relapsing multiple sclerosis (MS). Despite the short treatment period, cladribine has a long-lasting effect on disease activity even after recovery of lymphocyte counts, suggesting a yet undefined long-term immune modulating effect.
Objectives: Our aim was to provide a more profound understanding of the detailed effects of cladribine, also with regard to the patients' therapy response.
Design: We performed an open-labeled, explorative, prospective, single-arm study, in which we examined the detailed lymphocyte subset development of MS patients who received cladribine treatment over 2 years.
Methods: We performed in-depth profiling of the effects of cladribine on peripheral blood lymphocytes by flow cytometry, bulk RNA sequencing of sorted CD4+ T cells, CD8+ T cells, and CD19+ B cells as well as single-cell RNA sequencing of peripheral blood mononuclear cells in a total of 23 MS patients before and at different time points up to 24 months after cladribine treatment. Data were correlated with clinical and cranial magnetic resonance imaging (MRI) disease activity.
Results: Flow cytometry revealed a predominant and sustained reduction of memory B cells compared to other B cell subsets after cladribine treatment, whereas T cell subsets were slightly reduced in a more uniform pattern. The overall transcriptional profile of total blood B cells exhibited reduced expression of proinflammatory and T cell activating genes, while single-cell transcriptomics revealed that gene expression within each B cell cluster did not change over time. Stable patients displayed stronger reductions of selected memory B cell clusters as compared to patients with clinical or cerebral MRI disease activity.
Conclusion: We describe a pronounced and sustained effect of cladribine on the memory B cell compartment, and the resulting change in B cell subset composition causes a significant alteration of B cell transcriptional profiles resulting in reduced proinflammatory and T cell activating capacities. The extent of reduction in selected memory B cell clusters by cladribine may predict treatment response.
背景:克拉利宾是一种高效的免疫疗法,在两年内分两个短期疗程使用,可降低复发性多发性硬化症(MS)患者的复发率和疾病进展。尽管治疗时间较短,但即使在淋巴细胞计数恢复后,克拉利宾仍能对疾病活动产生长期影响,这表明克拉利宾具有尚未确定的长期免疫调节作用:我们的目的是更深入地了解克拉利宾的详细作用,以及患者的治疗反应:设计:我们进行了一项开放标签、探索性、前瞻性、单臂研究,研究了接受克拉利宾治疗两年以上的多发性硬化症患者淋巴细胞亚群的详细发展情况:我们通过流式细胞术、CD4+ T细胞、CD8+ T细胞和CD19+ B细胞的大量RNA测序以及外周血单核细胞的单细胞RNA测序,深入分析了克拉利宾对外周血淋巴细胞的影响。数据与临床和头颅磁共振成像(MRI)疾病活动相关:结果:流式细胞术显示,与其他 B 细胞亚群相比,记忆 B 细胞在克拉利宾治疗后主要持续减少,而 T 细胞亚群则以更均匀的模式略有减少。全血 B 细胞的整体转录谱显示促炎症基因和 T 细胞激活基因的表达减少,而单细胞转录组学显示,每个 B 细胞集群内的基因表达并没有随着时间的推移而改变。与有临床或脑磁共振成像疾病活动的患者相比,病情稳定的患者所选择的记忆B细胞集群减少得更厉害:我们描述了克拉利宾对记忆 B 细胞区系的明显而持续的影响,由此导致的 B 细胞亚群组成的变化引起了 B 细胞转录谱的显著改变,从而降低了促炎和激活 T 细胞的能力。克拉利宾对特定记忆 B 细胞群的抑制程度可预测治疗反应。
期刊介绍:
Therapeutic Advances in Neurological Disorders is a peer-reviewed, open access journal delivering the highest quality articles, reviews, and scholarly comment on pioneering efforts and innovative studies across all areas of neurology. The journal has a strong clinical and pharmacological focus and is aimed at clinicians and researchers in neurology, providing a forum in print and online for publishing the highest quality articles in this area.