Multimodal effects of CD40L blockade in multiple sclerosis: Insights from preclinical and clinical studies

Costimulatory signaling is essential for T-cell activation, tolerance, and immune homeostasis. Dysregulation of these pathways contributes to autoimmune diseases, including multiple sclerosis. Therapeutic targeting of costimulatory molecules, particularly the CD40–CD40L axis, has demonstrated clinical success in several autoimmune conditions, including multiple sclerosis. This review integrates mechanistic insights from experimental models with clinical data to examine the effects of CD40L blockade across diverse immune and central nervous system–resident cell populations. Preclinical models highlight the complex interplay between immune cells and central nervous system–resident cells beyond costimulatory signaling alone. Clinical mechanistic studies support CD40L blockade as a promising therapeutic strategy for multiple sclerosis.