Figure 2.

Strategies to target the CD40 ligand (CD40L)–CD40L dyad in experimental autoimmune encephalomyelitis (EAE). (A) Antagonistic CD40L antibodies limit detrimental T cell responses in multiple sclerosis (MS) by decreasing IFNγ production, reducing myelin peptide-specific delayed-type hypersensitivity responses, and limiting in effector T cell formation. In addition, antibody treatment enhances the production of the Th2 cytokine interleukin (IL)-4. (B,C) A novel strategy to target the CD40L–CD40 axis in monocytes and macrophages during EAE. The CD40L–CD40–TRAF6 axis activates the transcription factor NF-κB, which subsequently induces an inflammatory monocyte/macrophage phenotype that aggravates EAE. Small molecule-mediated inhibition of the CD40–TRAF6 interaction reduces ROS, TNFα, and IL6 production by macrophages and limits transendothelial migration of monocytes, thereby improving EAE in mice and rats.