Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

David Kavanagh, Sarah McGlasson, Alexa Jury, Jac Williams, Neil J Scolding, Chris Bellamy, Claudia Gunther, Diane Ritchie, Daniel P Gale, Yashpal S Kanwar, Rachel Challis, Holly Buist, James Overell, Belinda Weller, Oliver Flossmann, Mark Blunden, Eric P Meyer, Thomas Krucker, Stephen J W Evans, Iain L CampbellAndrew P Jackson, Siddharthan Chandran, David P J Hunt

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

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 therapies, with recent concern regarding the use of interferon 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 a such an association between type I interferon and TMA. We show the clinical phenotype of cases referred to a national centre 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 interferon toxicity. This includes specific microvascular pathological changes seen in patient biopsies, and is dependent on transcriptional activation of the interferon response through the type I interferon receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I interferon and thrombotic microangiopathy. As such, recombinant type I interferon therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation.
Original languageEnglish
Pages (from-to)2824-2833
Number of pages10
JournalBlood
Volume128
Issue number24
Early online date23 Sep 2016
DOIs
Publication statusPublished - 15 Dec 2016

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