Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature
Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature
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DOI：
10.1182/blood-2016-05-715987
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发表时间：
2016-12-15
期刊：
影响因子：
20.3
通讯作者：
Hunt, David P. J.
中科院分区：
文献类型：
--
作者：
Kavanagh, David;McGlasson, Sarah;Hunt, David P. J.
据报道，许多药物会导致血栓性微血管病(TMA)，但支持直接联系的证据往往很弱。特别是，TMA已被报道与重组I型干扰素(干扰素)治疗有关，最近有关干扰素在多发性硬化症患者中的使用受到关注。然而，两者之间的因果关系尚未得到证实。在这里，我们采用临床和实验相结合的方法来提供I型干扰素和TMA之间的这种联系的证据。我们表明，转诊到国家中心的病例的临床表型与直接剂量依赖的药物诱导的TMA一致。然后，我们证明了剂量依赖的微血管疾病在干扰素毒性的转基因小鼠模型中被看到。这包括患者活检组织中可见的特定微血管病变，并依赖于通过I型干扰素a/b受体(IFNAR)转录激活的干扰素反应。总之，我们的临床和实验结果提供了I型干扰素和TMA之间因果联系的证据。因此，对于发生这种并发症的患者，重组I型干扰素治疗应该在最早阶段停止，这意味着风险降低。
Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type IIFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon a/b receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation.