Modified recombinant human IgG1-Fc is superior to natural intravenous immunoglobulin at inhibiting immune-mediated demyelination.
Modified recombinant human IgG1-Fc is superior to natural intravenous immunoglobulin at inhibiting immune-mediated demyelination.
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修饰的重组人IgG 1-Fc在抑制免疫介导的脱髓鞘方面上级天然静脉注射免疫球蛋白。
DOI：
10.1111/imm.13341
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发表时间：
2021-09
期刊：
影响因子：
6.4
通讯作者：
Pleass RJ
中科院分区：
文献类型：
--
作者：
Baksmeier C;Blundell P;Steckel J;Schultz V;Gu Q;Da Silva Filipe A;Kohl A;Linnington C;Lu D;Dell A;Haslam S;Wang J;Czajkowsky D;Goebels N;Pleass RJ
静脉注射免疫球蛋白（IVIG）是一种治疗多种自身免疫性疾病的既定疗法。虽然来自IVIG的Fc片段在控制儿童免疫性血小板减少症方面显示出疗效，但其作用机制尚不清楚且存在争议。本研究的目的是在中枢神经系统-免疫界面的离体模型中使用进一步适应的Fc片段对脱髓鞘剖析IVIG效应器机制。使用来自转基因小鼠的器官型小脑切片培养物（OSC），我们用髓鞘少突胶质细胞糖蛋白（MOG）和补体特异性抗体诱导了广泛的免疫介导的脱髓鞘和少突胶质细胞损失。通过绿色荧光蛋白表达的实时成像、免疫组织化学和共聚焦显微镜评估适应的Fc片段的保护作用。半胱氨酸和聚糖适应性Fc片段以剂量依赖性方式保护OSC免于脱髓鞘，其中等摩尔浓度的IVIG或对照Fc无效。适应性Fc片段的保护作用部分归因于干扰补体介导的少突胶质细胞损伤。转录组分析排除了与炎症或先天免疫反应相关的特征。总之，我们的研究结果表明，重组仿生可以比IVIG在控制抗MOG抗体脱髓鞘方面至少有效200倍。当等摩尔浓度的IVIG或对照Fc无效时，适应性Fc片段以剂量依赖性方式保护抗体介导的脱髓鞘。适应性Fc片段的保护作用部分归因于干扰补体介导的少突胶质细胞损伤。
Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Although Fc fragments derived from IVIG have shown efficacy in controlling immune thrombocytopenia in children, the mechanisms of action are unclear and controversial. The aim of this study was to dissect IVIG effector mechanisms using further adapted Fc fragments on demyelination in an ex vivo model of the central nervous system–immune interface. Using organotypic cerebellar slice cultures (OSCs) from transgenic mice, we induced extensive immune‐mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective effects of adapted Fc fragments were assessed by live imaging of green fluorescent protein expression, immunohistochemistry and confocal microscopy. Cysteine‐ and glycan‐adapted Fc fragments protected OSC from demyelination in a dose‐dependent manner where equimolar concentrations of either IVIG or control Fc were ineffective. The protective effects of the adapted Fc fragments are partly attributed to interference with complement‐mediated oligodendroglia damage. Transcriptome analysis ruled out signatures associated with inflammatory or innate immune responses. Taken together, our findings show that recombinant biomimetics can be made that are at least two hundred‐fold more effective than IVIG in controlling demyelination by anti‐MOG antibodies. Adapted Fc fragments protect against antibody‐mediated demyelination in a dose‐dependent manner where equimolar concentrations of either IVIG or control Fc were ineffective. The protective effects of the adapted Fc fragments are partly attributed to interference with complement‐mediated oligodendroglia damage.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
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5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
影响因子：
38.1
作者：
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通讯作者：
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作者：
DePaula-Silva, Ana Beatriz;Gorbea, Carlos;Fujinami, Robert S.
通讯作者：
Fujinami, Robert S.
开发用于药物和疫苗应用的 IVIG 仿生物质 hexa-Fc。
影响因子：
4.6
作者：
Czajkowsky DM;Andersen JT;Fuchs A;Wilson TJ;Mekhaiel D;Colonna M;He J;Shao Z;Mitchell DA;Wu G;Dell A;Haslam S;Lloyd KA;Moore SC;Sandlie I;Blundell PA;Pleass RJ
通讯作者：
Pleass RJ