Abbadessa Gianmarco, Lepore Maria Teresa, Bruzzaniti Sara, Piemonte Erica, Miele Giuseppina, Signoriello Elisabetta, Perna Francesco, De Falco Chiara, Lus G, Matarese Giuseppe, Bonavita Simona, Galgani Mario
From the Department of Advanced Medical and Surgical Sciences (G.A., G. Miele, E.S., G.L., S. Bonavita), University of Campania Luigi Vanvitelli; Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G.Salvatore" - Consiglio Nazionale delle Ricerche (M.T.L., S. Bruzzaniti, G. Matarese, M.G.); Department of Molecular Medicine and Medical Biotechnologies (E.P., G. Matarese, M.G.); Department of Clinical Medicine and Surgery (F.P.), University of Naples "Federico II"; and UOC Biochimica Clinica - Ospedali dei Colli (C.D.F.), Naples, Italy.
Neurol Neuroimmunol Neuroinflamm. 2024 Jul;11(4):e200250. doi: 10.1212/NXI.0000000000200250. Epub 2024 Apr 25.
The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment.
In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8 T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8 T and NK lymphocytes as surrogate markers of anti-EBV activity.
We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8 T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8 T-cell proliferation in response to EBV antigenic peptides.
Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8 and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.
B细胞在导致复发型多发性硬化症（R-MS）的致病过程中的作用直到最近才得以阐明。抗CD20单克隆抗体的治疗效果为明确这一作用提供了关键步骤。事实上，抗CD20治疗也会改变其他未在细胞表面直接表达CD20的免疫细胞的数量和功能，这些细胞的活动可能在影响治疗效果的未知方面发挥作用。我们研究了奥瑞珠单抗治疗前后R-MS患者中细胞毒性淋巴细胞的表型和功能以及爱泼斯坦-巴尔病毒（EBV）特异性免疫反应。
在这项前瞻性研究中，我们收集了41例R-MS患者在开始使用奥瑞珠单抗前、治疗6个月和12个月后的血样，以评估免疫表型以及对CD8 T细胞和自然杀伤（NK）细胞细胞毒性功能的间接影响。此外，我们评估了CD8 T细胞和NK淋巴细胞的特异性抗EBV增殖反应，作为抗EBV活性的替代标志物。
我们观察到，虽然奥瑞珠单抗消耗了循环B细胞，但它也降低了CD8 T细胞和NK细胞上激活和迁移标志物的表达以及它们的体外细胞毒性活性。即使根据R-MS患者先前的疾病修饰治疗将其分组，在细胞毒性细胞中也观察到奥瑞珠单抗对免疫分子的类似调节模式。这些效应伴随着CD8 T细胞对EBV抗原肽反应的显著且选择性降低。
综上所述，我们的研究结果表明，奥瑞珠单抗在消耗B细胞的同时，会影响CD8和NK细胞的细胞毒性功能，其对髓鞘抗原交叉活性的降低可能也有助于其在MS治疗中的疗效。
