Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA; Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, NY, USA.
Exp Neurol. 2021 Jan;335:113488. doi: 10.1016/j.expneurol.2020.113488. Epub 2020 Sep 28.
The human myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (huMOG-EAE) model, generates B-cell driven demyelination in mice, making it a suitable multiple sclerosis model to study B cell depletion.
We investigated the effect of subcutaneous anti-CD20 antibody treatment on huMOG-EAE gray matter (GM) pathology.
C57Bl/6, 8-week old mice were immunized with 200 huMOG and treated with 50 μg/mouse of anti-CD20 antibody (n = 16) or isotype control (n = 16). Serial brain volumetric 9.4 T MRI scans was performed at baseline, 1 and 5 wkPI. Disease severity was measured by clinical disability score (CDS) and performance on rotarod test.
Anti-CD20 antibody significantly reduced brain volume loss compared with the isotype control across all timepoints longitudinally in the basal ganglia (p = 0.01), isocortex (p = 0.025) and thalamus (p = 0.023). The CDS was reduced significantly with anti-CD20 antibody vs. the isotype control at 3 (p = 0.003) and 4 (p = 0.03) wkPI, while a trend was observed at 5 (p = 0.057) and 6 (p = 0.086) wkPI. Performance on rotarod was also improved significantly at 3 (p = 0.007) and 5 (p = 0.01) wkPI compared with the isotype control. At cellular level, anti-CD20 therapy suppressed the percentage of proliferative nuclear antigen positive microglia in huMOG-EAE isocortex (p = 0.016). Flow cytometry confirmed that anti-CD20 antibody strongly depleted the CD19-expressing B cell fraction in peripheral blood mononuclear cells, reducing it from 39.7% measured in isotype control to 1.59% in anti-CD20 treated mice (p < 0.001).
Anti-CD20 antibody treatment delayed brain tissue neurodegeneration in GM, and showed clinical benefit on measures of disease severity in huMOG-EAE mice.
人类髓鞘少突胶质细胞糖蛋白诱导的实验性自身免疫性脑脊髓炎（huMOG-EAE）模型在小鼠中产生 B 细胞驱动的脱髓鞘，使其成为研究 B 细胞耗竭的合适多发性硬化症模型。
我们研究了皮下抗 CD20 抗体治疗对 huMOG-EAE 灰质（GM）病理学的影响。
C57Bl/6，8 周龄小鼠用 200 huMOG 免疫，并接受 50μg/只小鼠的抗 CD20 抗体（n=16）或同种型对照（n=16）治疗。基线、1 周和 5 周时进行连续的大脑容积 9.4T MRI 扫描。疾病严重程度通过临床残疾评分（CDS）和转棒试验表现来测量。
与同种型对照相比，抗 CD20 抗体在所有时间点均显著减少了基底节（p=0.01）、大脑皮层（p=0.025）和丘脑（p=0.023）的脑体积损失。与同种型对照相比，抗 CD20 抗体在 3（p=0.003）和 4（p=0.03）周时的 CDS 显著降低，而在 5（p=0.057）和 6（p=0.086）周时观察到趋势。与同种型对照相比，转棒试验的表现也在 3（p=0.007）和 5（p=0.01）周时显著改善。在细胞水平上，抗 CD20 治疗抑制了 huMOG-EAE 大脑皮层中增殖核抗原阳性小胶质细胞的百分比（p=0.016）。流式细胞术证实，抗 CD20 抗体强烈耗尽外周血单核细胞中表达 CD19 的 B 细胞亚群，使其从同种型对照中测量的 39.7%减少到抗 CD20 治疗小鼠中的 1.59%（p<0.001）。
抗 CD20 抗体治疗延迟了 GM 中的脑组织神经退行性变，并在 huMOG-EAE 小鼠的疾病严重程度测量上显示出临床益处。
