The role of α4 integrin in Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease: an infectious animal model for multiple sclerosis (MS)

Hirano, Yuta; Kobayashi, Kunitoshi; Tomiki, Hiroki; Inaba, Yuhji; Ichikawa, Motoki; Kim, Byung S.; Koh, Chang-Sung

Natalizumab, which is an antibody against α4 integrin, has been used for the treatment of multiple sclerosis (MS). In the present study, we investigated both the role of α4 integrin and the therapeutic effect of HCA3551, a newly synthesized orally active small-molecule α4 integrin antagonist, in the development of TMEV-induced demyelinating disease (TMEV-IDD). The mRNA levels of α4 integrins were significantly up-regulated in the CNS of mice with TMEV-IDD as compared with naïve mice (*p<0.05). HCA3551 treatment in the effector phase significantly suppressed both the clinical and histological development of TMEV-IDD. The number of infiltrating mononuclear inflammatory cells in the CNS was significantly decreased in the mice treated with HCA3551 (**p<0.01). The labeling indices for CD68 antigen and the absolute cell numbers of TNF-α-producing CD4(+) T cells and IFN-γ-producing CD8(+) T cells were significantly decreased in the CNS of mice treated with HCA3551 (*p<0.05). HCA3551 treatment in the effector phase might inhibit the binding of α4 integrin to VCAM-1, thereby decreasing the number of MNCs in the CNS.