Immune reconstitution and tolerance-inducing therapies as promising therapeutic approaches in multiple sclerosis

Abstract Objectives Multiple sclerosis (MS) is a complex, progressive neurodegenerative autoimmune disease and a major cause of neurological disability worldwide. MS affects approximately 2.8-3 million people, predominantly presenting as relapsing–remitting MS (RRMS) that frequently converts to secondary progressive disease, while effective options for progressive phenotypes remain limited. Methods This review reframes MS immunotherapy through a tolerance-centric paradigm, distinguishing continuous maintenance disease-modifying therapies (DMTs) from immune reconstitution therapies (IRTs) and emerging antigen-specific tolerance strategies. Results Classical immune reconstitution therapies, including alemtuzumab, cladribine, and autologous hematopoietic stem cell transplantation (aHSCT), have demonstrated durable disease control and prolonged periods of no evidence of disease activity (NEDA) in appropriately selected patients. This is accomplished through a finite course of lymphocyte depletion followed by qualitative immune repopulation that favors tolerogenic regulatory T (Treg) and regulatory B (Breg) cells over pathogenic Th1/Th17 clones. In contrast, maintenance DMTs (interferons, sphingosine-1-phosphate modulators, anti-CD20 monoclonals, natalizumab) suppress inflammation activity during continuous administration but lack durable immune reset. Building on IRT principles, next-generation cell-based therapies (tolerogenic dendritic cells (tolDCs), autologous Tregs, and mesenchymal stromal cells/extracellular vesicles (MSCs/EVs)), aim to induce precision, antigen-specific tolerance while minimizing systemic immunosuppression. These approaches hold promise for overcoming the limitations of chronic immunosuppression, providing durable disease control, and improving long-term patient outcomes. Discussion Collectively, immune reconstitution and tolerance-inducing therapies represent an emerging shift from lifelong disease control toward durable immune resetting and the possibility of sustained drug-free remission in MS.