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

Area of Science:

• Immunology
• Pharmacology
• Pathology

Background:

• Thrombotic microangiopathy (TMA) is a serious condition linked to various drugs.
• Recombinant type I interferon (IFN) therapies have been anecdotally associated with TMA, particularly in multiple sclerosis patients.
• A definitive causal link between type I IFN and TMA remains unproven.

Purpose of the Study:

• To investigate the causal association between type I interferon (IFN) and thrombotic microangiopathy (TMA).
• To provide clinical and experimental evidence supporting a direct link between type I IFN therapies and TMA development.

Main Methods:

• Clinical analysis of TMA cases referred to a national center.
• Development and study of a transgenic mouse model for IFN toxicity.
• Examination of microvascular pathological changes in patient biopsies and mouse models.
• Assessment of the role of type I interferon α/β receptor (IFNAR) signaling.

Main Results:

• Clinical presentation of referred cases uniformly indicated dose-dependent, drug-induced TMA.
• Transgenic mice exposed to IFN exhibited dose-dependent microvascular disease.
• Pathological changes in mice mirrored those observed in human patient biopsies.
• The observed microvascular disease was dependent on transcriptional activation via the type I interferon α/β receptor (IFNAR).

Conclusions:

• The study presents compelling clinical and experimental evidence establishing a causal relationship between type I interferon (IFN) and thrombotic microangiopathy (TMA).
• Recombinant type I IFN therapies should be discontinued promptly in patients presenting with TMA.
• These findings have significant implications for risk mitigation strategies in patients undergoing IFN treatment.