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

Abstract

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.

Notch Signaling Regulates Antigen Sensitivity of Naive CD4+ T Cells by Tuning Co-stimulation

“…DLL4- blocking mAbs suppress disease in models of multiple sclerosis, graft-versus-host disease, and transplantation (Takeichi et al, 2010; Tran et al, 2013; Ishida et al, 2011). Based on our findings that CD4 + T cell responses were impaired in the absence of DLL4 on APCs, we posit that the immune-suppressive effects of DLL4 mAb in these models were due to less-efficient T cell priming.…”

Regulation of innate and adaptive immunity by Notch

“…This inflammation-mediated demyelination disease of the central nervous system (CNS) can be induced by immunization with myelin antigens, viral infection or transfer of autoreactive T cells. Genetic and pharmacological interference with Notch signalling, as well as administration of blocking antibodies against Notch receptors or Delta-like ligand 4 (DLL4), impeded progression of the disease, resulting in reduced clinical severity 74,75,84,91,92,[118][119] . The mechanisms by which blockage of Notch signalling ameliorates EAE are not fully understood and require further investigation.…”

Therapeutic effects of anti-Delta1 mAb on Theiler's murine encephalomyelitis virus-induced demyelinating disease

“…These IL-10 producing splenocytes may not affect TMEV-IDD. Our Delta4 study in TMEV-IDD also revealed that the number of infiltrating MNCs in spinal cord was decreased, and absolute cell numbers of IFN-γ-, TNF-α-and IL-10-producing cells were significantly reduced in mice treated with anti-Delta4 mAb in effector phase compared with control mice (Takeichi et al, 2010). On the other hand, the number of IL-17-producing cells tended to increase in mice treated with anti-Delta1 mAb rather than control mice treated with non-specific IgG.…”

“…We previously demonstrated that administration of anti-Delta4 mAb suppressed the development of TMEV-IDD (Takeichi et al, 2010). In the present study, we have investigated the role of Delta1 using a neutralizing anti-Delta1 mAb in the development of TMEV-IDD.…”

“…In another study, there was a significant decrease in the clinical score in the anti-Delta1 mAb-treated mice in EAE, while blockade of Jagged1 deteriorated the disease (Elyaman et al, 2007). Furthermore, we previously demonstrated that administration of anti-Delta4 mAb suppressed the development of TMEV-IDD (Takeichi et al, 2010). Here, we have described for the first time that blocking the Delta1-induced Notch signaling by anti-Delta1 mAb in the effector phase markedly suppresses the development of TMEV-IDD and decreases the number of infiltrating cells, suggesting that Delta1-induced Notch signaling may play a critical role in infiltrating inflammatory mononuclear cells (MNCs) in TMEV-IDD and Delta1 could be a novel therapeutic target in human multiple sclerosis.…”