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实验得到了提示，其中抑制Δ-分泌酶和抗体阻断δ样配体（DLL）1下调炎性T细胞细胞因子应答。然而，我们最近首次证明DLL 4功能的阻断抑制了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，DLL 4的作用是调节致脑炎性T细胞趋化因子受体的表达和随后的运输到中枢神经系统，而不是调节Th 1或Th 17反应，尽管DLL 4已被报道具有该功能。DLL 4似乎是参与EAE发病机制的重要分子，因为它具有比DLL 1或Jagged 1更大的调节T细胞活化的能力。一起寻找 我们的初步数据表明，用抗-CD 3、抗-CD 28和重组DLL 4而不是重组DLL 1或Jagged 1上调趋化因子受体活化T细胞，为在EAE中追求DLL 4介导的Notch调节T细胞迁移作为疾病发病机制中的关键因素提供了强有力的理论基础。因此，我们的总体假设是DLL 4通过调节T细胞效应物运输机制来调节EAE的发展。提出了三个具体的目标来直接测试这一想法，确定原始观察背后的机制，并将这些发现转化为多发性硬化症（MS）的新疗法。 在具体目标1中，我们将确定DLL 4调节T细胞趋化因子受体表达的机制。在具体目标2中，我们将确定内皮DLL 4是否与T细胞Notch细胞接合以调节T细胞趋化因子受体表达。在具体目标3中， 确定抗DLL 4治疗功效和DLL 4在表位扩散中的作用，作为复发性EAE的机制。因此，拟议的工作具有很高的生物医学意义，并将引入概念和技术创新的MS研究领域。

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.