Amelioration of autoimmune neuroinflammation by the fusion molecule Fn14·TRAIL

Abstract

Abstract Background Multiple sclerosis (MS) is a, T cell-mediated autoimmune disease, the management of which remains challenging. The recently described fusion protein, Fn14·TRAIL, combining the extracellular domain of Fn14 (capable of blocking the pro-inflammatory TWEAK ligand) fused to the extracellular domain of the TRAIL ligand (capable of sending apoptotic signals through its receptors on activated inflammatory cells) was designed to modulate the immune system as an anti-inflammatory agent. The present study explores the efficacy of this purified protein as an anti-inflammatory agent, using the animal model of MS - experimental autoimmune encephalomyelitis (EAE). Methods EAE was induced by myelin oligodendrocyte glycoprotein (MOG). Fn14·TRAIL or vehicle were injected daily for 4 to 16 days, at different time points after disease induction. Animals were examined daily and evaluated for EAE clinical signs. Lymphocytes were analyzed for ex vivo re-stimulation, cytokine secretion, transcription factor expression and subtype cell analysis. Spinal cords were checked for inflammatory foci. The Mann- Whitney rank sum test, Student’s t-test or ANOVA were used for statistical analysis. Results Significant improvement of EAE in the group treated with Fn14·TRAIL was noted from day 6 of disease onset and lasted until the end of follow-up (day 40 from disease induction), even in animals treated for 4 days only. Clinical improvement was linked to decreased lymphocyte infiltrates in the central nervous system (CNS) and to decreased Th1 and Th17 responses and to increased number of T- regulatory in the treated mice. No liver or kidney toxicity was evident. In vitro assays established the ability of Fn14·TRAIL to induce apoptosis of T cell lines expressing TRAIL receptors and TWEAK. Conclusions In this study we established the potency of Fn14·TRAIL, a unique fusion protein combining two potentially functional domains, in inhibiting the clinical course of EAE, even when given for a short time, without apparent toxicity. These findings make Fn14·TRAIL a highly promising agent to be used for targeted amelioration of neuro-inflammatory processes, as well as other autoimmune pathologies.