奥瑞珠单抗对原发性进展型多发性硬化症患者血液白细胞的影响。
Effect of Ocrelizumab in Blood Leukocytes of Patients With Primary Progressive MS.
机构信息
From the Immunology Department (J.I.F.-V., P.E.W.-D., E.R.-M., E.R., N.V., L.M.V.), Ramon y Cajal University Hospital, Madrid, Spain; Neurologic Clinic and Policlinic (J.K., A.M.), Departments of Medicine, Biomedicine, and Clinical Research, University Hospital Basel, University of Basel, Switzerland; Neurology Department (E.M., S.S.d.l.M., J.M., L.C.-F.), Ramon y Cajal University Hospital, Madrid; Neurology Department (V.M.-L., P.S.), La Princesa University Hospital, Madrid; Multiple Sclerosis and Clinical Neuroimmunology Unit (J.M.-L., E.C.-G.), Virgen de la Arrixaca University Hospital, Murcia; Multiple Sclerosis Unit (G.I.), Vithas Nisa Sevilla Hospital; Neurology Department (F.G.-G.), Valencia Clinic University Hospital; Center of Neuroimmunology (A.S., Y.B.), Neurology Department, Clínic of Barcelona Hospital, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Institut de Neurociències, Universitat de Barcelona; Neurology Department (Y.A.), Getafe University Hospital, Madrid; Neurology Department (L.B.), Arnau de Vilanova Hospital, Lleida; Neurology Department (C.Í.), Lozano Blesa Clinic University Hospital, Zaragoza; Neurology Department (I.G.-S.), Alvaro Cunqueiro Hospital, Vigo; Neurology Department (L.A.R.d.A.), Fuenlabrada University Hospital, Madrid, Spain.
出版信息
Neurol Neuroimmunol Neuroinflamm. 2021 Jan 6;8(2). doi: 10.1212/NXI.0000000000000940. Print 2021 Mar 4.
OBJECTIVE
To analyze the changes induced by ocrelizumab in blood immune cells of patients with primary progressive MS (PPMS).
METHODS
In this multicenter prospective study including 53 patients with PPMS who initiated ocrelizumab treatment, we determined effector, memory, and regulatory cells by flow cytometry at baseline and after 6 months of therapy. Wilcoxon matched paired tests were used to assess differences between baseline and 6 months' results. Values were corrected using the Bonferroni test.
RESULTS
Ocrelizumab reduced the numbers of naive and memory B cells ( < 0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNFα) ( < 0.0001 in all cases). By contrast, the proportions of plasmablasts and B cells producing GM-CSF and TNFα increased significantly, suggesting the need for treatment continuation. We also observed a decrease in CD20 T-cell numbers ( < 0.0001) and percentages ( < 0.0001), and a clear remodeling of the T-cell compartment characterized by relative increases of the naive/effector ratios in CD4 ( = 0.002) and CD8 ( = 0.002) T cells and relative decreases of CD4 ( = 0.03) and CD8 ( = 0.004) T cells producing interferon-gamma. Total monocyte numbers increased ( = 0.002), but no changes were observed in those producing inflammatory cytokines. The immunologic variations were associated with a reduction of serum neurofilament light chain (sNfL) levels ( = 0.008). The reduction was observed in patients with Gd-enhanced lesions at baseline and in Gd- patients with baseline sNfL >10 pg/mL.
CONCLUSIONS
In PPMS, effector B-cell depletion changed T-cell response toward a low inflammatory profile, resulting in decreased sNfL levels.
目的
分析奥瑞珠单抗对原发性进展型多发性硬化症（PPMS）患者血液免疫细胞的影响。
方法
本项多中心前瞻性研究纳入了 53 名接受奥瑞珠单抗治疗的 PPMS 患者，我们通过流式细胞术在基线和治疗 6 个月时测定效应、记忆和调节细胞。采用 Wilcoxon 配对检验评估基线和 6 个月时的结果差异。采用 Bonferroni 检验校正值。
结果
奥瑞珠单抗降低了幼稚 B 细胞和记忆 B 细胞的数量（均<0.0001）以及产生白细胞介素（IL）-6、IL-10、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和肿瘤坏死因子-α（TNFα）的 B 细胞数量（所有情况下均<0.0001）。相反，浆母细胞和产生 GM-CSF 和 TNFα 的 B 细胞的比例显著增加，提示需要继续治疗。我们还观察到 CD20 T 细胞数量（<0.0001）和比例（<0.0001）下降，T 细胞区室发生明显重塑，表现为 CD4（=0.002）和 CD8（=0.002）T 细胞中的幼稚/效应比相对增加，以及 CD4（=0.03）和 CD8（=0.004）T 细胞产生干扰素-γ的比例相对降低。总单核细胞数量增加（=0.002），但产生炎症细胞因子的单核细胞无变化。免疫变化与血清神经丝轻链（sNfL）水平降低（=0.008）相关。在基线时存在钆增强病变的患者和基线 sNfL>10pg/ml 的 Gd-患者中观察到这种降低。
结论
在 PPMS 中，效应 B 细胞耗竭改变了 T 细胞对低炎症表型的反应，导致 sNfL 水平降低。
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