Department of Neurology, Christian Doppler Medical Center, Paracelsus Medical University, 5020 Salzburg, Austria.
Department of Neurology, Multiple Sclerosis Center, Center of Clinical Neuroscience, Carl Gustav Carus University Hospital, Technical University Dresden, 01307 Dresden, Germany.
Cells. 2021 Nov 10;10(11):3116. doi: 10.3390/cells10113116.
Cladribine (CLAD) is a deoxyadenosine analogue prodrug which is given in multiple sclerosis (MS) as two short oral treatment courses 12 months apart. Reconstitution of adaptive immune function following selective immune cell depletion is the presumed mode of action. In this exploratory study, we investigated the impact of CLAD tablets on immune cell surface molecules for adhesion (CAMs) and costimulation (CoSs) in people with MS (pwMS). We studied 18 pwMS who started treatment with CLAD and 10 healthy controls (HCs). Peripheral blood mononuclear cells were collected at baseline and every 3 months throughout a 24-month period. We analysed ICAM-1, LFA-1, CD28, HLADR, CD154, CD44, VLA-4 (CD49d/CD29), PSGL-1 and PD-1 with regard to their expression on B and T cells (T helper (Th) and cytotoxic T cells (cT)) and surface density (mean fluorescence intensity, MFI) by flow cytometry. The targeted analysis of CAM and CoS on the surface of immune cells in pwMS revealed a higher percentage of ICAM-1 (B cells, Th, cT), LFA-1 (B cells, cT), HLADR (B cells, cT), CD28 (cT) and CD154 (Th). In pwMS, we found lower frequencies of Th and cT cells expressing PSGL-1 and B cells for the inhibitory signal PD-1, whereas the surface expression of LFA-1 on cT and of HLADR on B cells was denser. Twenty-four months after the first CLAD cycle, the frequencies of B cells expressing CD44, CD29 and CD49d were lower compared with the baseline, together with decreased densities of ICAM-1, CD44 and HLADR. The rate of CD154 expressing Th cells dropped at 12 months. For cT, no changes were seen for frequency or density. Immune reconstitution by oral CLAD was associated with modification of the pro-migratory and -inflammatory surface patterns of CAMs and CoSs in immune cell subsets. This observation pertains primarily to B cells, which are key cells underlying MS pathogenesis.
克拉屈滨（CLAD）是一种脱氧腺苷类似物前体药物，在多发性硬化症（MS）中作为两个相隔 12 个月的短程口服治疗方案给予。选择性免疫细胞耗竭后适应性免疫功能的重建被认为是其作用模式。在这项探索性研究中，我们研究了 CLAD 片剂对 MS 患者（pwMS）免疫细胞表面黏附分子（CAMs）和共刺激分子（CoSs）的影响。我们研究了 18 名开始接受 CLAD 治疗的 pwMS 和 10 名健康对照（HCs）。在 24 个月的时间内，每 3 个月采集一次外周血单核细胞。我们通过流式细胞术分析了细胞间黏附分子-1（ICAM-1）、淋巴细胞功能相关抗原-1（LFA-1）、CD28、人类白细胞抗原-DR（HLADR）、CD154、CD44、血管细胞黏附分子-4（CD49d/CD29）、P 选择素糖蛋白配体-1（PSGL-1）和程序性死亡蛋白-1（PD-1）在 B 和 T 细胞（辅助性 T 细胞（Th）和细胞毒性 T 细胞（cT））上的表达及其表面密度（平均荧光强度，MFI）。对 pwMS 免疫细胞表面 CAM 和 CoS 的靶向分析显示，ICAM-1（B 细胞、Th、cT）、LFA-1（B 细胞、cT）、HLADR（B 细胞、cT）、CD28（cT）和 CD154（Th）的表达更高。在 pwMS 中，我们发现 Th 和 cT 细胞表达 PSGL-1 和 B 细胞表达抑制性信号 PD-1 的频率较低，而 cT 细胞上的 LFA-1 表达和 B 细胞上的 HLADR 表达更密集。第一个 CLAD 周期后 24 个月，与基线相比，B 细胞表达 CD44、CD29 和 CD49d 的频率更低，同时 ICAM-1、CD44 和 HLADR 的密度也降低。12 个月时，表达 CD154 的 Th 细胞的频率下降。对于 cT，频率或密度没有变化。口服 CLAD 免疫重建与免疫细胞亚群中 CAM 和 CoS 的促迁移和促炎表面模式的改变有关。这种观察主要涉及 B 细胞，B 细胞是 MS 发病机制的关键细胞。
