Ameliorating effects of anti-Dll4 mAb on Theiler's murine encephalomyelitis virus-induced demyelinating disease.

We examined the role of Notch ligand Delta-like 4 (Dll4) in the development of Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD). Treatment with mAb to Dll4, especially during the effector phase, resulted in significant suppression of the disease development both clinically and histologically. The number of infiltrating mononuclear inflammatory cells in the spinal cords was also decreased in mice treated with anti-Dll4 mAb. Semi-quantitative analysis of mRNA by using real-time PCR revealed that mRNAs of T(h)1-derived cytokines such as IFN-gamma and T(h)17-derived cytokines such as IL-17 were decreased in mice treated with anti-Dll4 mAb, whereas those of T(h)2-derived cytokines such as IL-4 and IL-10 were not. Flow cytometric analysis of cytokines indicated that there were no significant differences between mAb-treated mice and control mice in the relative frequency of splenic T(h)1 and T(h)2. However, absolute cell numbers of T(h)1-derived cytokine-producing cells in spinal cord were markedly decreased in mice treated with anti-Dll4 mAb in effector phase compared with control mice treated with non-specific IgG. These data suggest that Dll4 is critically involved in the pathogenesis of TMEV-IDD and that antibodies to Dll4 could be used as a novel therapeutic treatment of demyelinating diseases such as human multiple sclerosis.