From the Laboratories of Neuroimmunology (A.M., V.P., S.P., M.C., S.J., L.O., C.P., R.A.D), Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Switzerland; Service of Neurology (V.P., R.B.-V., M.T., C.P., R.A.D.), Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Switzerland; Paris Brain Institute (V.P.), Lubetzki-Stankoff group of Myelination, France; Service of Immunology and Allergy (M.M., C.F.), Department of Medicine, Lausanne University Hospital and University of Lausanne, Switzerland.
Neurol Neuroimmunol Neuroinflamm. 2023 Jan 30;10(2). doi: 10.1212/NXI.0000000000200084. Print 2023 Mar.
Depleting CD20 B cells is the primary mechanism by which ocrelizumab (OCRE) is efficient in persons with multiple sclerosis (pwMS). However, the exact role of OCRE on other immune cell subsets directly or indirectly remains elusive. The purpose of this study is to characterize the dynamics of peripheral immune cells of pwMS on OCRE.
We collected blood samples from 38 pwMS before OCRE onset (T0) and at 6 and 12 months (T6, T12) after initiation. To cover the immune cell diversity, using mass cytometry time of flight, we designed a 38-parameter panel to analyze B, T, and innate immune cell markers and CNS migratory markers. In parallel, viral-specific CD8 T-cell responses were assessed by the quantification of interferon-γ secretion using the enzyme-linked immunospot assay on cytomegalovirus, Epstein-Barr virus, and influenza stimulations.
Beside B-cell depletion, we observed a loss in memory CD8CD20 and central memory CD8 T cells but not in CD4CD20 T cells already at T6 and T12 ( < 0.001). The loss of memory CD8 T cells correlated with a lower CXCR3 expression ( < 0.001) and CNS-related LFA-1 integrin expression ( < 0.001) as well as a reduced antiviral cellular immune response observed at both time points ( < 0.001). Of note, we did not observe major changes in the phenotype of the other cell types studied. Seven of 38 (18.4%) patients in our cohort presented with infections while on OCRE; 4 of which were switched from dimethyl fumarate. Finally, using a mixed linear model on mass cytometry data, we demonstrated that the immunomodulation induced by previous disease-modifying therapies (DMTs) was prolonged over the period of the study.
In addition to its well-known role on B cells, our data suggest that OCRE also acts on CD8 T cells by depleting the memory compartment. These changes in CD8 T cells may be an asset in the action of OCRE on MS course but might also contribute to explain the increased occurrence of infections in these patients. Finally, although more data are needed to confirm this observation, it suggests that clinicians should pay a special attention to an increased infection risk in pwMS switched from other DMTs to OCRE.
奥瑞珠单抗（OCRE）通过耗竭 CD20 B 细胞在多发性硬化症（pwMS）患者中发挥作用。然而，OCRE 对其他免疫细胞亚群的直接或间接确切作用仍不清楚。本研究旨在研究 OCRE 对 pwMS 外周免疫细胞的动态影响。
我们在 OCRE 起始前（T0）、起始后 6 个月（T6）和 12 个月（T12）收集了 38 名 pwMS 的血液样本。为了涵盖免疫细胞的多样性，我们使用液质联用飞行时间技术设计了一个 38 个参数的面板，以分析 B、T 和固有免疫细胞标志物以及 CNS 迁移标志物。同时，我们通过酶联免疫斑点法检测巨细胞病毒、EB 病毒和流感刺激后干扰素-γ的分泌，评估病毒特异性 CD8 T 细胞反应。
除了 B 细胞耗竭外，我们还观察到记忆性 CD8 CD20 和中央记忆性 CD8 T 细胞在 T6 和 T12 时已经减少（<0.001），而 CD4 CD20 T 细胞未见减少。记忆性 CD8 T 细胞的减少与较低的 CXCR3 表达（<0.001）和与 CNS 相关的 LFA-1 整合素表达（<0.001）以及在两个时间点观察到的降低的抗病毒细胞免疫反应相关（<0.001）。值得注意的是，我们未观察到研究中其他细胞类型的表型发生重大变化。我们队列中有 7 名（18.4%）患者在接受 OCRE 治疗时发生感染，其中 4 名患者从二甲基富马酸酯转换而来。最后，我们使用混合线性模型对液质联用数据进行分析，结果表明先前疾病修饰治疗（DMTs）的免疫调节作用在研究期间延长。
除了其在 B 细胞上的已知作用外，我们的数据还表明 OCRE 还通过耗竭记忆性细胞亚群作用于 CD8 T 细胞。这些 CD8 T 细胞的变化可能是 OCRE 对 MS 病程作用的优势，但也可能有助于解释这些患者感染发生率增加的原因。最后，尽管需要更多的数据来证实这一观察结果，但它表明临床医生应特别注意从其他 DMT 转换为 OCRE 的 pwMS 感染风险增加。
