Nogo Receptors as Therapeutic Targets in a Model of 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，是美国年轻人中最常见的非创伤性神经残疾原因。当中枢神经系统形成炎症灶，导致脱髓鞘和对邻近轴突的损害时，疾病的恶化就会发生。绝大多数患者最终进入进展期，在此期间，他们逐渐但不可阻挡地积累残疾。临床残疾与轴突损伤和神经元丢失的测量最密切相关。目前用于治疗多发性硬化症的疾病修改疗法(DMT)没有一种直接保护神经元或轴突免受损伤或一旦发生就逆转损害。髓鞘相关抑制物(MAI)，如Nogo、MAG和OMGp，是一类结合轴突上同源受体(包括Nogo受体(NgRs)和配对免疫球蛋白样受体B(PirB))以抑制神经元萌发和突触可塑性的蛋白质家族。此外，NgR1信号复合体的一种成分LINGO-1与少突胶质前体细胞的结合抑制了少突胶质细胞的分化和重新髓鞘形成。最近，NgRs被发现在炎症中发挥作用。我们认为MAIS与它们的受体(NgR1、NgR2和PirB)之间的相互作用都能促进实验性自身免疫性脑脊髓炎(EAE)小鼠的神经炎症和神经和髓鞘修复。我们建议的具体目的如下：1)探讨诱骗受体NgROMNI在临床EAE发生发展中的作用。我们将测试NgROMNI，一种新开发的Nogo受体Fc融合蛋白，它阻断MAI与NgRs和PirB的结合，在复发-缓解和进展型EAE中的治疗效果。除了NgROMNI对临床病程的影响外，我们还将评估其对髓鞘和轴突完整性以及自身免疫T细胞启动的影响。2)探讨MAI-PirB相互作用是否促进髓鞘免疫小鼠白细胞亚群的活化、分化和中枢神经系统转运。PirB是表达在单核细胞和其他白细胞上的免疫球蛋白超家族成员，最近被发现是Nogo、MAG和OMgp的受体。在这个目标中，我们将验证我们的工作假设，即PirB信号进入髓系细胞对于EAE的临床表现是必要的。具体地说，我们预测PirB缺乏或阻断将抑制分化和 外周树突状细胞启动脑源性T细胞的生物学活性 抑制自身免疫性脱髓鞘期间在中枢神经系统损伤中积聚的单核细胞、巨噬细胞和激活的小胶质细胞的活性。3)研究NgROMNI对EAE小鼠神经元萌发和髓鞘再生的影响。为了区分NgROMNI对神经胶质细胞和轴突的直接作用和对造血细胞的直接作用，NgROMNI将在复发缓解期EAE(远远超过神经炎性浸润物的建立)和慢性进展期EAE的高峰期后使用。在免费实验中，EAE将在WT--&gt；NGR-/-和WT--&gt；WT骨髓嵌合小鼠身上进行比较。最终，我们希望这些临床前研究的结果将为NGR诱骗蛋白或其他MAI拮抗剂在MS中的临床试验奠定基础。如果成功，NGR拮抗剂将成为治疗MS的第一类具有抗炎和神经保护/神经恢复特性的药物。

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 CNS resulting in demyelination and damage to neighboring axons. The vast majority of patients ultimately enter a progressive phase during which they gradually, but inexorably, accumulate disability. Clinical disability correlates most strongly with measures of axonal damage and neuronal loss. None of the disease modifying therapies (DMT) currently used to treat MS directly protect neurons or axons from injury or reverse damage once it occurs. Myelin associated inhibitors (MAIs), such as Nogo, MAG, and OMgp, constitute a family of proteins that bind cognate receptors (including Nogo receptors (NgRs) and paired immunoglobulin-like receptor B (PirB)) on axons to suppress neuronal sprouting and synaptic plasticity. Furthermore, engagement of LINGO-1, a component of the NgR1 signaling complex, on oligodendrocyte progenitor cells, inhibits oligodendrocyte differentiation and remyelination. More recently, NgRs have been found to play a role in inflammation. We propose that interactions between MAIs and their receptors (NgR1, NgR2, and PirB) both promote neuroinflammation and curtail neural and myelin repair in mice with experimental autoimmune encephalomyelitis (EAE), widely used as a model of MS. The specific aims of our proposal are as follows: 1) To investigate the role of the decoy receptor, NgROMNI, in the development of clinical EAE. We will test the therapeutic efficacy of NgROMNI, a newly developed Nogo receptor Fc fusion protein that blocks binding of MAIs to NgRs and PirB, in relapsing-remitting and progressive forms of EAE. In addition to the impact of NgROMNI on the clinical course, we will assess its effects on myelin and axonal integrity and autoimmune Tcell priming. 2) To determine whether MAI-PirB interactions facilitate the activation, differentiation and CNS trafficking of leukocyte subsets in myelin immunized mice. PirB, a member of the immunoglobulin superfamily expressed on monocytes and other leukocytes, was recently identified as a receptor for Nogo, MAG and OMgp. In this aim, we will test our working hypothesis that PirB signaling into myeloid cells is necessary for the clinical manifestation of EAE. Specifically, we predict that PirB deficiency or blockade will inhibit the differentiation and biological activities of peripheral dendritic cells that prime encephalitogenic T cells, as well as suppress the activities of monocytes, macrophages and activated microglia that accumulate in CNS lesions during autoimmune demyelination. 3) To characterize the effects of NgROMNI on neuronal sprouting and remyelination in mice with EAE. In order to distinguish the direct effects of NgROMNI on glial cells and axons from those on hematopoietic cells, NgROMNI will be administered after peak disease in relapsing remitting EAE (well past the establishment of neuroinflammatory infiltrates) and during chronic stages of progressive EAE. In complimentary experiments EAE will be compared in WT-->NgR-/- and WT-->WT bone marrow chimeric mice. Ultimately we hope that the results of these preclinical studies will set the stage for clinical trals of NgR decoy proteins or other MAI antagonists in MS. If successful, NgR antagonists will represent the first class of agents used to treat MS that have both anti-inflammatory and neuroprotective/ neurorestorative properties.