Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature.
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.
National Renal Complement Therapeutics Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
David
D
Kavanagh
Medical Research Council Institute of Genetics and Molecular Medicine and.
Sarah
0000-0002-0077-0991
S
McGlasson
Medical Research Council Institute of Genetics and Molecular Medicine and.
Alexa
A
Jury
Centre for Clinical Brain Sciences, Edinburgh University, Edinburgh, United Kingdom.
Jac
J
Williams
Institute of Clinical Neurosciences, University of Bristol, Bristol, United Kingdom.
Neil
N
Scolding
Department of Renal Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Chris
C
Bellamy
Department of Dermatology, University Hospital, Technical University Dresden, Dresden, Germany.
Claudia
C
Gunther
Centre for Clinical Brain Sciences, Edinburgh University, Edinburgh, United Kingdom.
Diane
D
Ritchie
Centre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom.
Daniel P
DP
Gale
Feinberg School of Medicine, Northwestern University, Chicago, IL.
Yashpal S
YS
Kanwar
National Renal Complement Therapeutics Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
Rachel
R
Challis
Department of Cellular Pathology, Royal Victoria Hospital, Newcastle upon Tyne, United Kingdom.
Holly
H
Buist
Institute of Neurological Sciences, Glasgow University, Glasgow, United Kingdom.
James
J
Overell
Centre for Clinical Brain Sciences, Edinburgh University, Edinburgh, United Kingdom.
Belinda
B
Weller
Royal Berkshire Hospital, Reading, United Kingdom.
Oliver
O
Flossmann
Barts and the London National Health Service Trust, London, United Kingdom.
Mark
M
Blunden
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
Eric P
EP
Meyer
The Scripps Research Institute, La Jolla, CA.
Thomas
T
Krucker
London School of Hygiene & Tropical Medicine, London, United Kingdom; and.
Stephen J W
SJ
Evans
School of Molecular Bioscience, University of Sydney, Sydney, Australia.
Iain L
IL
Campbell
Medical Research Council Institute of Genetics and Molecular Medicine and.
Andrew P
AP
Jackson
Centre for Clinical Brain Sciences, Edinburgh University, Edinburgh, United Kingdom.
Siddharthan
S
Chandran
Medical Research Council Institute of Genetics and Molecular Medicine and.|Centre for Clinical Brain Sciences, Edinburgh University, Edinburgh, United Kingdom.
David P J
0000-0003-4230-0207
DP
Hunt
D000818:Animals; D001706:Biopsy; D006801:Humans; D007370:Interferon Type I / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008822:Mice, Transgenic; D055806:Microvessels / Q000187:drug effects* / Q000648:ultrastructure; D009103:Multiple Sclerosis / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity; D057049:Thrombotic Microangiopathies / Q000139:chemically induced*
D007370:Interferon Type I
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