Preclinical studies of a MADCAM-Fc fusion protein in multiple sclerosis

描述（由申请人提供）： 多发性硬化症（MS）是一种中枢神经系统（CNS）的自身免疫性疾病，是美国年轻人神经系统残疾最常见的非创伤性原因。当视神经、脑或脊髓中形成炎性病灶时，疾病加重，导致脱髓鞘和邻近轴突损伤。MS病变形成的关键步骤是粘附分子介导的白细胞从血流迁移到CNS。目前的提议测试了我们的假设，即靶向阻断特定的粘附分子相互作用（在CNS浸润T细胞上表达的a4 b7和在发炎的CNS血管上表达的MAdCAM-1之间）将防止MS小鼠模型（实验性自身免疫性脑脊髓炎或EAE）中自身免疫性脱髓鞘的恶化。为此，我们设计了一种嵌合融合蛋白（MAdCAM-1-Fc），由MAdCAM-1-Fc的胞外结构域连接到小鼠免疫球蛋白重链的Fc区组成。该试剂阻止MAdCAM-1结合表达a4 b7的T细胞。我们将确定MAdCAM-1-Fc或对照融合蛋白的全身给药是否抑制EAE的复发或进展。此外，在其安全性测试中，我们将向感染甲病毒的小鼠施用MAdCAM-1-Fc，并确定该治疗是否阻碍病毒清除和/或触发CNS中潜伏病毒的再活化。我们建议的具体目标如下：1。目的研究小鼠复发性和慢性实验性自身免疫性脑脊髓炎（EAE）过程中a4 b7在CNS浸润CD 4 + T细胞上的时空表达及其同源配体MAdCAM-1在CNS血管内皮上的时空表达。设计另外的实验以检查诱导髓鞘特异性效应细胞上的a4 b7和CNS内皮细胞上的MAdCAM-1的表达的炎性因子。2.研究a4 b7阻断在复发和慢性EAE模型中的治疗结果。我们将比较一种新型MAdCAM-1-Fc重组融合蛋白（特异性阻断α 4 β 7整联蛋白）与其他粘附分子阻断剂在病程不同时间点给药的疗效。3.表征全身性a4 b7阻断对小鼠CNS急性病毒感染和再活化潜伏病毒感染的影响。我们将使用甲病毒感染的小鼠模型来比较MAdCAM-1-Fc和其他融合蛋白对抗病毒免疫和免疫监视的作用。

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is the most common non-traumatic cause of neurological disability among young adults in the United States. Exacerbations of the disease occur when inflammatory foci form in the optic nerves, brain or spinal cord, resulting in demyelination and damage to neighboring axons. A critical step in the formation of MS lesions is adhesion molecule mediated transmigration of leukocytes from the bloodstream into the CNS. The current proposal tests our hypothesis that targeted blockade of a particular adhesion molecule interaction (between a4b7, expressed on CNS-infiltrating T cells, and MAdCAM-1, expressed on inflamed CNS blood vessels) will prevent exacerbations of autoimmune demyelination in a mouse model of MS (experimental autoimmune encephalomyelitis or EAE). To do so, we have engineered a chimeric fusion protein (MAdCAM-1-Fc), composed of the extracellular domain of MAdCAM-1-Fc linked to the Fc region of mouse immunoglobulin heavy chain. This reagent prevents MAdCAM-1 from binding a4b7 expressing T cells. We will determine whether systemic administration of MAdCAM-1-Fc or control fusion proteins suppresses relapses or progression of EAE. Furthermore, in a test of its safety, we will administer MAdCAM-1-Fc to mice infected with an alphavirus and determine whether the treatment impedes viral clearance and/ or triggers reactivation of latent virus in the CNS. The specific aims of our proposal are as follows: 1. To study the temporal and spatial expression of a4b7 on CNS infiltrating CD4+ T cells and its cognate ligand, MAdCAM-1, on CNS vascular endothelium during the course of relapsing and chronic experimental autoimmune encephalomyelitis (EAE) in mice. Additional experiments are designed to examine the inflammatory factors that induce expression of a4b7 on myelin-specific effector cells and MAdCAM-1 on CNS endothelial cells. 2. To investigate the therapeutic consequences of a4b7 blockade in both relapsing and chronic EAE models. We will compare the therapeutic efficacy of a novel MAdCAM-1-Fc recombinant fusion protein (that specifically blocks a4b7 integrin) versus other adhesion molecule blocking agents, when given at different time points in the disease course. 3. To characterize the effects of systemic a4b7 blockade on acute viral infection of the CNS and reactivated latent viral infection in mice. We will use a mouse model of alphavirus infection to compare the effects of MAdCAM-1-Fc and other fusion proteins on anti-viral immunity and immunosurveillance.