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，是美国年轻人神经系统残疾最常见的非创伤性原因。当CNS中形成炎性病灶时，疾病加重，导致脱髓鞘和邻近轴突损伤。绝大多数患者最终进入一个渐进阶段，在此期间，他们逐渐但不可避免地积累残疾。临床残疾与轴突损伤和神经元损失的测量最密切相关。目前用于治疗MS的疾病修饰疗法（DMT）中没有一种直接保护神经元或轴突免受损伤或一旦发生逆转损伤。髓磷脂相关抑制剂（迈斯），如Nogo、MAG和OMgp，构成结合轴突上的同源受体（包括Nogo受体（NgR）和成对的免疫球蛋白样受体B（PirB））以抑制神经元发芽和突触可塑性的蛋白质家族。此外，NGR 1信号复合物的一种成分LINGO-1在少突胶质细胞祖细胞上的参与抑制了少突胶质细胞的分化和髓鞘再生。最近，已发现NgR在炎症中起作用。我们提出，迈斯和它们的受体（NgR 1，NgR 2和PirB）之间的相互作用都促进神经炎症和减少神经和髓鞘修复的小鼠实验性自身免疫性脑脊髓炎（EAE），广泛用作MS的模型。我们的建议的具体目的如下：1）调查诱饵受体，NgROMNI，在临床EAE的发展中的作用。我们将测试NgROMNI（一种新开发的Nogo受体Fc融合蛋白，其阻断迈斯与NgR和PirB的结合）在复发缓解型和进行性形式的EAE中的治疗功效。除了NgROMNI对临床过程的影响外，我们还将评估其对髓鞘和轴突完整性以及自身免疫性T细胞引发的影响。2)确定MAI-PirB相互作用是否促进髓磷脂免疫小鼠中白细胞亚群的活化、分化和CNS运输。PirB是在单核细胞和其他白细胞上表达的免疫球蛋白超家族的成员，最近被鉴定为Nogo、MAG和OMgp的受体。在这个目标中，我们将测试我们的工作假设，即PirB信号传导到骨髓细胞是EAE临床表现所必需的。具体地，我们预测PirB缺陷或阻断将抑制分化， 引发致脑炎性T细胞的外周树突状细胞的生物活性，以及 抑制单核细胞、巨噬细胞和活化的小胶质细胞的活性，这些细胞在自身免疫性脱髓鞘过程中积聚在CNS病变中。3)描述NgROMNI对EAE小鼠神经元发芽和髓鞘再生的影响。为了区分NgROMNI对神经胶质细胞和轴突的直接作用与对造血细胞的直接作用，NgROMNI将在复发缓解型EAE的疾病高峰后（远远超过神经炎性浸润的建立）和进行性EAE的慢性阶段期间施用。在补充实验中，将在WT-->NgR-/-和WT-->WT骨髓嵌合小鼠中比较EAE。最终，我们希望这些临床前研究的结果将为NgR诱饵蛋白或其他MAI拮抗剂在MS中的临床试验奠定基础。如果成功，NgR拮抗剂将代表用于治疗MS的第一类药物，其具有抗炎和神经保护/神经恢复特性。

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.