DLL4 Regulation of T Cell Migration in EAE

描述（由申请人提供）：Notch受体系统在中枢神经系统（CNS）脱髓鞘疾病中的重要性已经通过抑制-分泌酶和抗体阻断δ - like配体（DLL） 1下调炎症T细胞细胞因子反应的实验得到证实。然而，我们最近首次证明阻断DLL4功能可抑制临床实验性自身免疫性脑脊髓炎（EAE）的发展。我们的数据表明，DLL4的作用是调节脑源性T细胞趋化因子受体的表达和随后向中枢神经系统的运输，而不是调节Th1或Th17的反应，尽管DLL4已被报道具有这一功能。与DLL1或Jagged 1相比，DLL4具有更强的调节T细胞活化的能力，因此DLL4似乎是参与EAE发病机制的重要分子。这一发现

DESCRIPTION (provided by applicant): The importance of the Notch receptor system in central nervous system (CNS) demyelinating disease has been suggested by experiments where inhibition of ¿-secretase and antibody blocking of Delta-Like Ligand (DLL) 1 down-regulated inflammatory T cell cytokine responses. However, we were the first to recently demonstrate that blockade of DLL4 function inhibited the development of clinical experimental autoimmune encephalomyelitis (EAE). Our data suggested that the role of DLL4 was to regulate encephalitogenic T cell chemokine receptor expression and subsequent trafficking to the CNS and not regulation of either Th1 or Th17 responses although DLL4 has been reported to have that function. DLL4 appears to be a significant molecule involved in the pathogenesis of EAE as it has a greater ability than DLL1 or Jagged 1 to regulate T cell activation. That finding together with our preliminary data indicating that T cell activation with anti-CD3, anti-CD28 and recombinant DLL4, but not recombinant DLL1 or Jagged1, up-regulated chemokine receptors provides strong rationale to pursue DLL4- mediated Notch regulation of T cell migration in EAE as a critical element in the pathogenesis of disease. Therefore, our overall hypothesis is that DLL4 regulates EAE development by modulating T cell effector trafficking mechanisms. Three specific aims are proposed to directly test this idea, determine the mechanism behind the original observation and translate these findings into a novel therapy for multiple sclerosis (MS). In specific aim 1 we will determine the mechanism behind DLL4 regulation of T cell chemokine receptor expression. In specific aim 2 we will determine whether endothelial DLL4 engagement with T cell Notch cells to regulate T cell chemokine receptor expression. In specific aim 3 we will determine anti-DLL4 treatment efficacy and the role of DLL4 in epitope spreading as a mechanism of relapsing EAE. The proposed work therefore has high biomedical significance and will introduce conceptual and technical innovations to the area of MS research.