Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Front Immunol. 2021 Oct 28;12:706278. doi: 10.3389/fimmu.2021.706278. eCollection 2021.
Alemtuzumab is a highly effective treatment for relapsing-remitting multiple sclerosis. It selectively targets the CD52 antigen to induce profound lymphocyte depletion, followed by recovery of T and B cells with regulatory phenotypes. We previously showed that regulatory T cell function is restored with cellular repletion, but little is known about the functional capacity of regulatory B-cells and peripheral blood monocytes during the repletion phase. In this study (ClinicalTrials.gov ID# NCT03647722) we simultaneously analyzed the change in composition and function of both regulatory lymphocyte populations and distinct monocyte subsets in cross-sectional cohorts of MS patients prior to or 6, 12, 18, 24 or 36 months after their first course of alemtuzumab treatment. We found that the absolute number and percentage of cells with a regulatory B cell phenotype were significantly higher after treatment and were positivity correlated with regulatory T cells. In addition, B cells from treated patients secreted higher levels of IL-10 and BDNF, and inhibited the proliferation of autologous CD4CD25 T cell targets. Though there was little change in monocytes populations overall, following the second annual course of treatment, CD14 monocytes had a significantly increased anti-inflammatory bias in cytokine secretion patterns. These results confirmed that the immune system in alemtuzumab-treated patients is altered in favor of a regulatory milieu that involves expansion and increased functionality of multiple regulatory populations including B cells, T cells and monocytes. Here, we showed for the first time that functionally competent regulatory B cells re-appear with similar kinetics to that of regulatory T-cells, whereas the change in anti-inflammatory bias of monocytes does not occur until after the second treatment course. These findings justify future studies of all regulatory cell types following alemtuzumab treatment to reveal further insights into mechanisms of drug action, and to identify key immunological predictors of durable clinical efficacy in alemtuzumab-treated patients.
阿仑单抗是一种治疗复发缓解型多发性硬化症的高效疗法。它选择性地靶向 CD52 抗原，诱导强烈的淋巴细胞耗竭，随后 T 和 B 细胞恢复具有调节表型。我们之前表明，随着细胞补充，调节性 T 细胞功能得到恢复，但在补充阶段，调节性 B 细胞和外周血单核细胞的功能能力知之甚少。在这项研究中（ClinicalTrials.gov ID# NCT03647722），我们同时分析了多发性硬化症患者在接受阿仑单抗首次治疗前或治疗后 6、12、18、24 或 36 个月的横断面队列中调节性淋巴细胞和不同单核细胞亚群的组成和功能变化。我们发现，治疗后具有调节性 B 细胞表型的细胞绝对数和百分比显著升高，并且与调节性 T 细胞呈正相关。此外，来自治疗患者的 B 细胞分泌更高水平的 IL-10 和 BDNF，并抑制自身 CD4CD25 T 细胞靶标的增殖。尽管单核细胞总体上变化不大，但在第二次年度治疗后，CD14 单核细胞的细胞因子分泌模式表现出抗炎偏向的显著增加。这些结果证实，阿仑单抗治疗患者的免疫系统发生改变，有利于涉及 B 细胞、T 细胞和单核细胞等多种调节性群体的扩张和增强功能的调节环境。在这里，我们首次表明，功能正常的调节性 B 细胞以与调节性 T 细胞相似的动力学重新出现，而单核细胞抗炎偏向的变化直到第二次治疗后才发生。这些发现证明了在阿仑单抗治疗后对所有调节性细胞类型进行进一步研究的合理性，以揭示药物作用机制的进一步见解，并确定阿仑单抗治疗患者持久临床疗效的关键免疫学预测因素。
