Gilch Sabine, Wopfner Franziska, Renner-Müller Ingrid, Kremmer Elisabeth, Bauer Christine, Wolf Eckhard, Brem Gottfried, Groschup Martin H, Schätzl Hermann M
Gene Center Munich, Max von Pettenkofer-Institute for Virology, Ludwig-Maximilians-University of Munich, Feodor-Lynen-Strasse 25, D-81377 Munich, Germany.
J Biol Chem. 2003 May 16;278(20):18524-31. doi: 10.1074/jbc.M210723200. Epub 2003 Mar 11.
Prion diseases are neurodegenerative infectious disorders for which no prophylactic regimens are known. In order to induce antibodies/auto-antibodies directed against surface-located PrP(c), 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 PrP(Sc) synthesis. We show that polyclonal antibodies are binding to surface-located PrP(c), 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 PrP(Sc) conversion process. Our data point to the possibility of developing means for an active immunoprophylaxis against prion diseases.
朊病毒疾病是一类神经退行性感染性疾病，目前尚无已知的预防方案。为了诱导针对位于表面的PrP(c)的抗体/自身抗体，我们使用了在大肠杆菌中重组表达的小鼠朊病毒蛋白的共价连接二聚体。以二聚体PrP作为免疫原，我们能够有效克服PrP野生型小鼠对鼠PrP的自身耐受性，且不产生明显的副作用。用兔产生的多克隆抗PrP抗体或小鼠产生的自身抗体处理朊病毒感染的小鼠细胞，可显著抑制内源性PrP(Sc)的合成。我们发现多克隆抗体与位于表面的PrP(c)结合，从而干扰朊病毒的生物发生。在完整IgG分子存在的情况下，这种效应更为明显，与Fab片段不同，完整IgG分子似乎能诱导表面PrP发生显著的交联。此外，当比较兔和PrP野生型小鼠诱导产生的抗体时，我们发现了针对不同表位的免疫反应。仅在小鼠自身抗体的情况下，发现了针对PrP一个区域的免疫反应，据报道该区域参与PrP(Sc)的转化过程。我们的数据表明，有可能开发出针对朊病毒疾病的主动免疫预防方法。
