Polyclonal anti-PrP auto-antibodies induced with dimeric PrP interfere efficiently with PrPSc propagation in prion-infected cells
Polyclonal anti-PrP auto-antibodies induced with dimeric PrP interfere efficiently with PrPSc propagation in prion-infected cells
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DOI：
10.1074/jbc.m210723200
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发表时间：
2003-05-16
影响因子：
4.8
通讯作者：
Schätzl, HM
中科院分区：
文献类型：
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作者：
Gilch, S;Wopfner, F;Schätzl, HM
朊病毒疾病是神经退行性感染性疾病，目前尚无预防方案。为了诱导针对表面定位的PrPc的抗体/自身抗体，我们使用了在大肠杆菌中重组表达的鼠朊蛋白共价连接二聚体。采用二聚体PrP作为免疫原，可以有效克服PrP野生型小鼠对小鼠PrP的自身耐受性，且无明显副作用。用兔多克隆抗prp抗体或小鼠自身抗体处理朊病毒感染的小鼠细胞，可显著抑制内源性PrPSc的合成。我们发现多克隆抗体与表面定位的PrPc结合，从而干扰朊病毒的生物发生。这种效应在完整的IgG分子存在时更为明显，与Fab片段不同，IgG分子似乎诱导了表面PrP的显著交联。此外，通过比较兔和PrP野生型小鼠诱导的抗体，我们发现了针对不同表位的免疫应答。仅在小鼠的自身抗体情况下，发现了一种针对PrP区域的免疫反应，据报道，该区域参与了PrPSc转化过程。我们的数据指出了开发针对朊病毒疾病的主动免疫预防手段的可能性。
Prion diseases are neurodegenerative infectious disorders for which no prophylactic regimens are known. In order to induce antibodies/auto-antibodies directed against surface-located PrPc, we used a covalently linked dimer of mouse prion protein expressed recombinantly in Escherichia coli. Employing dimeric PrP as an immunogen we were able to effectively overcome autotolerance against murine PrP in PrP wild-type mice without inducing obvious side effects. Treatment of prion-infected mouse cells with polyclonal anti-PrP antibodies generated in rabbit or auto-antibodies produced in mice significantly inhibited endogenous PrPSc synthesis. We show that polyclonal antibodies are binding to surface-located PrPc, thereby interfering with prion biogenesis. This effect is much more pronounced in the presence of full IgG molecules, which, unlike Fab fragments, seem to induce a significant cross-linking of surface PrP. In addition, we found immune responses against different epitopes when comparing antibodies induced in rabbits and PrP wild-type mice. Only in the auto-antibody situation in mice an immune reaction against a region of PrP is found that was reported to be involved in the PrPSc conversion process. Our data point to the possibility of developing means for an active immunoprophylaxis against prion diseases.