Wandinger Klaus-Peter, Lünemann Jan D, Wengert Oliver, Bellmann-Strobl Judith, Aktas Orhan, Weber Alexandra, Grundström Eva, Ehrlich Stefan, Wernecke Klaus-D, Volk Hans-Dieter, Zipp Frauke
Institute of Neuroimmunology, Charité University Hospital, Schumannstrasse 20/21, 10117, Berlin, Germany.
Lancet. 2003 Jun 14;361(9374):2036-43. doi: 10.1016/S0140-6736(03)13641-0.
Many patients with multiple sclerosis do not respond to interferon beta, which is widely used as an immunomodulatory treatment in this disease. We aimed to assess the functional relevance of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), which is upregulated on incubation with interferon beta, for clinical treatment response.
We quantified gene expression longitudinally by realtime-PCR of the peripheral immune cells of 82 patients with multiple sclerosis. In a first cohort of 62 patients, 20 were classified as first-year responders since they did not have relapses during treatment with interferon beta 1a; 19 were classified as first-year non-responders; and 23 developed neutralising antibodies to interferon beta. A second cohort, also characterised by MRI, consisted of 11 patients on interferon beta 1a and nine patients who were not treated. Concentrations of soluble TRAIL were determined by ELISA in serum samples of nine non-treated patients, 49 patients before treatment (29 responders, 20 non-responders), as well as longitudinally in a subset of 23 patients.
In both patient cohorts, drug-responders could be distinguished from non-responders by early and sustained induction of TRAIL (p<0.0001, each). In the presence of neutralising antibodies, initial upregulation of TRAIL expression was subsequently abrogated. Raised concentrations of soluble TRAIL in patients' serum samples before the start of treatment allowed prediction of the treatment response in the first year (ROC analysis with area under the curve 0.879 [0.785-0.974]).
Our data suggest that TRAIL expression is a candidate for pretreatment assessment and might thus be used as a prognostic marker of treatment response to interferon beta in multiple sclerosis. Furthermore, our observations have implications for the development of future immunoregulatory strategies in multiple sclerosis therapy.
许多多发性硬化症患者对干扰素β没有反应，而干扰素β在该疾病中被广泛用作免疫调节治疗药物。我们旨在评估与干扰素β孵育后上调的肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）与临床治疗反应的功能相关性。
我们通过实时聚合酶链反应（PCR）对82例多发性硬化症患者外周免疫细胞中的基因表达进行纵向定量分析。在第一个队列的62例患者中，20例被归类为第一年反应者，因为他们在用1a型干扰素β治疗期间未出现复发；19例被归类为第一年无反应者；23例产生了针对干扰素β的中和抗体。第二个队列同样通过磁共振成像（MRI）进行特征描述，包括11例接受1a型干扰素β治疗的患者和9例未接受治疗的患者。通过酶联免疫吸附测定（ELISA）法测定9例未治疗患者、49例治疗前患者（29例反应者，20例无反应者）血清样本中可溶性TRAIL的浓度，并对23例患者的一个亚组进行纵向检测。
在两个患者队列中，药物反应者与无反应者可通过TRAIL的早期和持续诱导来区分（均p<0.0001）。在存在中和抗体的情况下，TRAIL表达的初始上调随后被消除。患者治疗开始前血清样本中可溶性TRAIL浓度升高可预测第一年的治疗反应（曲线下面积为0.879 [0.785 - 0.974]的ROC分析）。
我们的数据表明，TRAIL表达是预处理评估的一个候选指标，因此可能用作多发性硬化症患者对干扰素β治疗反应的预后标志物。此外，我们的观察结果对未来多发性硬化症治疗中免疫调节策略的开发具有启示意义。
