Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease
Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease
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DOI：
10.1096/fj.01-0994fje
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发表时间：
2002-06-01
期刊：
影响因子：
4.8
通讯作者：
Pease, LR
中科院分区：
文献类型：
--
作者：
Mitsunaga, Y;Ciric, B;Pease, LR
某些来自单克隆丙种球蛋白病患者的人血清含有诱导脱髓鞘疾病动物髓鞘修复的因子。我们假设抗体在功能上区分一个患者的血清与另一个。然而，汇集的正常多克隆人IgM抗体也诱导髓鞘再生。特异性抗体是血清的生物活性成分的证据缺失，因为毫无疑问，抗体分子的纯制剂不能通过分级分离产生。为了明确证明抗体是患者血清的生物活性组分，生成重组抗体用于生物测定中的评价。体内髓鞘再生的诱导需要毫克量的抗体。因此，表达系统被工程化以在体外表达高滴度的重组人IgM抗体。评价所得重组抗体（rHIgM22）在慢性进行性脱髓鞘疾病的泰勒病毒小鼠模型中诱导髓鞘再生的能力。我们证明，一个单一的重组单克隆抗体概括了患者血清的关键特征，包括结合特异性，在体外少突胶质细胞中钙信号的诱导，以及在体内脱髓鞘斑块内髓鞘修复的诱导。rHIgM22抗体提供了一个新的场所的髓鞘再生的机制的分析，并可能证明在脱髓鞘疾病的治疗有用。
Certain human sera from patients with monoclonal gammopathies contain factors that induce myelin repair in animals with demyelinating disease. We hypothesize that antibodies functionally distinguish the serum of one patient from another. However, pooled normal polyclonal human IgM antibodies also induce remyelination. Definitive proof that specific antibodies are the biologically active components of serum is missing because unquestionably pure preparations of antibody molecules cannot be generated by fractionation. To demonstrate definitively that antibody is the biologically active component of patient serum, recombinant antibody was generated for evaluation in bioassays. The induction of remyelination in vivo requires milligram quantities of antibody. Consequently, an expression system was engineered to express high-titer, recombinant human IgM antibodies in vitro. A resulting recombinant antibody (rHIgM22) was evaluated for its ability to induce remyelination in the Theiler's virus mouse model of chronic-progressive demyelinating disease. We demonstrate that a single recombinant monoclonal antibody recapitulates the key characteristics of patient serum, including binding specificity, the induction of calcium signals in oligodendrocytes in vitro, and the induction of myelin repair within demyelinated plaques in vivo. The rHIgM22 antibody provides a new venue for the analysis of mechanisms governing remyelination and may prove useful in the treatment of demyelinating diseases.