期刊
BLOOD
卷 128, 期 24, 页码 2824-2833出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-05-715987
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资金
- Wellcome Trust [WT101153MA]
- Academy of Medical Sciences
- Deutsche Forschungsgemeinschaft [KFO 249/GU1212/1-1, GU1212/1-2]
- Medical Research Council
- National Health Medical Research Council [512407]
- National Institutes of Health, National Institute of Mental Health [MH47680]
- MRC [MC_PC_U127580972] Funding Source: UKRI
- Medical Research Council [MC_PC_U127580972] Funding Source: researchfish
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.
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