Autoimmune diseases affect 5 % of individuals in developed countries and hence comprise an important factor in health care [1]. Over 100 autoimmune entities are known and many of these are characterized by an acute or chronic organ-specific inflammation, which is driven by a targeted immune response against self-antigens. The central nervous system (CNS) has long been seen as an immune privileged organ. However, immune cells efficiently monitor the organ and several different inflammatory diseases of the CNS are recognized to be driven by an autoreactive, antigen-specific immune response [2].

The majority of autoimmune diseases of the CNS is characterized by a chronic inflammation causing either relapsing neurological dysfunction or chronic accumulation of disability or both. Consequently, they cause a high burden for patients and society at large. During the last two decades, the development of immune therapies for conditions like multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD) has been very successful with substantial improvements in reducing the risk for relapses and associated worsening of disease and improving the long-term outcome for patients [3], [4], [5]. In addition, several late stage clinical trials are ongoing in NMOSD (eg. for satralizumab, rozimab) and in MS (eg. for remibrutinib, fenebrutinib, frexalimab, vidofludimus calcium). Currently approved therapies for autoimmune disease of the CNS are broadly immunosuppressive or immunomodulatory, and the higher therapeutic efficacy came at the cost of safety and tolerability aspects for patients as a consequence of inhibiting physiologic immune responses.

Therapeutic strategies aiming at induction of antigen-specific immune tolerance offer the opportunity to treat a pathogenic autoreactive immune response with high specificity and without impeding essential protective function of the healthy immune system [6].

In this review, we will summarize the current concepts and prospects of therapeutic immune tolerance in autoimmune disease of the CNS with a focus on MS, NMOSD and MOG-antibody associated disease (MOGAD) and discuss the lessons learned from prior successes and failures of therapeutic approaches in patients with CNS autoimmune disease, most importantly in MS. With regard to a detailed description of the pathophysiology of these autoimmune diseases of the central nervous system we refer to other article in this series [7], [8], [9].