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

David Kavanagh, Sarah McGlasson, Alexa Jury, Jac Williams, Neil 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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 (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 I IFN 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 α/β 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.

Original languageEnglish (US)
Pages (from-to)2824-2833
Number of pages10
JournalBlood
Volume128
Issue number24
DOIs
StatePublished - Dec 15 2016

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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