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

Kavanagh, D; McGlasson, S; Jury, A; Williams, J; Scolding, N; Bellamy, C; Gunther, C; ... Hunt, DPJ; + view all (2016) Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood , 128 (24) pp. 2824-2833. 10.1182/blood-2016-05-715987. Green open access

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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 (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 dosedependent 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.

Type: Article
Title: Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood-2016-05-715987
Publisher version: http://doi.org/10.1182/blood-2016-05-715987
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1539135
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