Therapeutic immune tolerance for central nervous system autoimmune diseases – Prospects, challenges and pitfalls

Abstract

Autoimmune diseases of the central nervous system (CNS), including multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), are characterized by chronic inflammation driven by autoreactive immune responses against CNS antigens. Successes in the development of efficacious immunotherapies are hampered by the risks of broad immunosuppression and the consequences of compromising physiological immune functions. Antigen-specific immune tolerance offers a promising alternative by selectively silencing pathogenic immune responses while preserving global immune competence. Advances in understanding of pathophysiology and target antigens in multiple sclerosis, neuromyleitis optica spectrum disroders (NMOSD) myelin oligondendrocyte protein (MOG) antibody associated disease (MOGAD) have enabled the development of antigen-based tolerization strategies. These approaches primarily act through restoration of peripheral tolerance via modulation of autoreactive T and B cell responses. Clinical trials in MS and NMOSD have provided critical insights into key challenges of translation and clinical development, including optimal antigen selection, route of administration, patient stratification and trial design constraints. Future progress in MS, NMO and MOGAD will also depend on precise characterization of immunodominant epitopes and the development of standardized biomarkers of tolerance induction and their integration in novel trial designs. Successful induction of durable, antigen-specific immune tolerance would represent a paradigm shift in treating CNS autoimmunity, enabling disease-specific, safe, and sustained remission without generalized immunosuppression.