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

Kavanagh, D. et al. (2016) Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature. Blood, 128(24), pp. 2824-2833. (doi: 10.1182/blood-2016-05-715987) (PMID:27663672)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Overell, Dr James
Authors: Kavanagh, D., McGlasson, S., Jury, A., Williams, J., Scolding, N., Bellamy, C., Gunther, C., Ritchie, D., Gale, D. P., Kanwar, Y. S., Challis, R., Buist, H., Overell, J., Weller, B., Flossmann, O., Blunden, M., Meyer, E. P., Krucker, T., Evans, S. J.W., Campbell, I. L., Jackson, A. P., Chandran, S., and Hunt, D. P.J.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Blood
Publisher:American Society of Hematology
ISSN (Online):1528-0020
Published Online:23 September 2016

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