Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) characterized by neuroinflammation, neurodegeneration and impaired repair mechanisms that lead to neurological disability. The crux of MS is the patient's own immune cells attacking self-antigens in the CNS, namely the myelin sheath that protects nerve cells of the brain and spinal cord. Restoring antigen-specific tolerance via therapeutic vaccination is an innovative and exciting approach in MS therapy. Indeed, leveraging the body's attempt to prevent autoimmunity, i.e., tolerization, focuses on the underlying cause of the disease and could be the key to solving neuroinflammation. In this perspective, antigen-specific vaccination targets only the detrimental and aberrant immune response against the specific disease-associated antigen(s) involved while retaining the capacity of the immune system to respond to unrelated antigens. We review the experimental approaches of tolerance-inducing vaccination in relapsing and progressive forms of MS that have reached the clinical development phase, including vaccination with autologous T cells, autologous tolerogenic dendritic cells, T cell receptor peptide vaccination, altered peptide ligand, ATX-MS-1467, cluster of differentiation (CD)-206-targeted liposomal myelin basic protein peptides and DNA vaccination. Failures, successes and future directions are discussed.

Fig. 1

Possible modes of action of tolerance-inducing therapeutic approaches in multiple sclerosis (MS). (1) Although the exact cause of MS remains unknown, proteins within the axon-surrounding myelin sheath, such as myelin oligodendrocyte protein (MOG), myelin basic protein (MBP), and proteolipid protein (PLP), are important targets of the autoreactive immune response. Furthermore, the progression of MS and the occurrence of relapses are associated with “epitope spreading,” a process characterized by loss of tolerance against endogenous antigens released during an inflammatory or auto-immune exacerbation. (2) Following administration, myelin-derived antigens, such as peptides, apitopes, or encoded by a DNA vaccine, are engulfed, processed, and presented by antigen-presenting cells, including Langerhans cells and DCs. (3) Presentation of myelin-derived antigen by DCs in the absence of costimulatory molecules, may result in the deletion of myelin-reactive T cells. (4) In addition, tolerance-inducing therapeutic approaches can induce so-called infectious tolerance by antigen-specific expansion of regulatory T cells (Treg) and are capable of counteracting epitope spreading (Adapted from Neuron Hand-tuned by Quasar Jarosz/CC BY-SA 3.0)