The Aryl Hydrocarbon Receptor as a regulator of CNS autoimmunity

Abstract

Abstract Therapeutic approaches aimed at controlling the balance between effector T cells and regulatory T cells in an antigen-specific manner are of high clinical significance in the field of autoimmunity. The aryl hydrocarbon receptor (AhR) has been identified as a key regulator of the adaptive immune system and thus represents a strong targetable candidate for the induction of immune tolerance. Here, we report the generation of a novel liposomal platform to co-administer a tolerogenic AhR ligand, ITE, and an autoimmune disease-specific T cell antigen. Liposomes containing ITE and a T-cell epitope from myelin oligodendrocyte glycoprotein (MOG)35–55 are taken up by dendritic cells and induce a tolerogenic transcriptional program which promotes the differentiation and expansion of long-lasting antigen-specific regulatory T cells. Treatment with these liposomes almost completely prevented the development of experimental autoimmune encephalomyelitis (EAE), an experimental model of relapsing-remitting multiple sclerosis (MS), and reversed symptoms in mice with ongoing EAE. This disease suppression was associated with the expansion of antigen-specific FoxP3+ regulatory T cells (Treg cells) and type 1 regulatory T cells (Tr1 cells) as well as the suppression of CNS-infiltrating effector T cells. Furthermore, treatment with liposomes containing ITE and MOG reversed symptoms of disease in chronic progressive EAE in nonobese diabetic mice, an experimental model resembling several aspects of secondary progressive MS. Taken together, these results suggest that our liposomes represent a novel therapeutic platform to induce antigen-specific tolerance for the treatment of autoimmune diseases.