Developing interferon-β as a safe in vivo experimental-medicine model of human inflammation.

BACKGROUND

Inflammation is increasingly implicated in a wide range of neuropsychiatric and neurodegenerative disorders from depression to dementia. Compelling evidence for an inflammatory role in these disorders includes experimental-medicine studies with IFN-α and endotoxin, alongside therapeutic benefits observed with anti-cytokine agents.

AIM: To develop and characterise a new, safe in-vivo mild inflammatory response that is titratable, elicits robust host sickness manifestations within an experimentally tractable timeframe, and has minimal cardiovascular effects, avoiding the requirement for continuous cardiac monitoring and ensuring applicability across diverse experimental contexts and participant groups, from the young to the elderly.

METHODS

Using a randomized, blinded, placebo-controlled, repeated measures cross-over design, physiological, behavioural, cytokine, cellular and transcriptomic immune responses were collected from 30 healthy volunteers (15 young (18-34) and 15 older (60-75) years) on two separate occasions, once after 100 µg subcutaneous IFN-β (EXTAVIA®) and once after subcutaneous saline (placebo) injection.

RESULTS

IFN-β increased ∼15-fold at 4 h and 9-fold at 6½ hours and rapidly induced anticipated increases in negative mood, tiredness, tension and sickness symptoms and reduced vigour (all p < 0.01) without serious side effects. It was associated with a modest increase in temperature (mean: +1.1C) and heart rate (mean: +11 bpm) but no change in blood-pressure or cardiovascular instability. IL-6, TNF-α, neutrophil to lymphocyte ratio and monocyte count all showed significant increases (all p < 0.05). Transcriptomic analyses confirmed activation of classical Interferon signalling pathways as well as Toll-like Receptor (TLR), Inflammasome, Pyroptosis, MyD88 and a variety of other host response pathways that have been implicated in the pathophysiology of neuropsychiatric or neurodegenerative disorders.

CONCLUSIONS

IFN-β is a safe, robust new experimental model of mild inflammation that can be safely used to induce transient changes in systemic inflammation in healthy individuals from 18-75 years. Modulation of diverse immunological processes suggests it could be a valuable new experimental medicine tool across neuropsychiatric and neurodegenerative disorders.