Immunoregulation of Myelin Specific T Lymphocytes

髓磷脂特异性 T 淋巴细胞的免疫调节

• 批准号: 10343790
• 负责人: ARTHUR A. VANDENBARK
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343790
• 关键词: Acute; Address; Animal Model; Applications Grants; Axon; Binding; Biological; CNS Demyelinating Autoimmune Diseases; CX3CL1 gene; CXCL1 gene; CXCL12 gene; CXCR4 gene; Cells; Chronic; Clinical; Clinical Trials; Complex; Coupled; Designer Drugs; Disease; Dopachrome isomerase; Experimental Autoimmune Encephalomyelitis; Female; Funding; Future; Generations; Genotype; Goals; HLA-DR2 Antigen; Health; Histologic; Homologous Gene; Human; IL8RB gene; Immune; Immunoglobulins; Individual; Inflammatory; Interferon Type II; Interleukin-17; Interleukin-2; Kinetics; Knockout Mice; Laboratories; Ligands; Light; Macrophage Activation; Methamphetamine use disorder; Migration Inhibitory Factor; Monoclonal Antibodies; Multiple Sclerosis; Mus; Myelin; Myeloid Cells; Neuraxis; Neurofilament-L; Neurons; Paralysed; Pathogenicity; Pathway interactions; Patients; Peptides; Persons; Phase; Phosphotransferases; Process; Production; Recovery; Regenerative pathway; Resources; Risk; Rodent; Role; Severities; Severity of illness; Signal Transduction; Solid; Spleen; Stress; Stroke; System; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; Transgenic Mice; Traumatic Brain Injury; Treatment Efficacy; Triad Acrylic Resin; Variant; chemokine; commercialization; complement pathway; cytokine; design; extracellular; healing; immunoregulation; improved; insight; interest; male; member; migration; mouse model; multiple sclerosis treatment; neurofilament; neuroprotection; novel; oligodendrocyte precursor; receptor; remyelination; repaired; response; screening

Multiple sclerosis (MS) is a devastating chronic, demyelinating autoimmune diseases of the central nervous system (CNS). Two key cytokines/chemokines thought to drive the early inflammatory stage of MS to a chronic progressive phase are macrophage Migration Inhibitory Factor (MIF) and its homolog D-Dopachrome Tautomerase (D-DT). Our laboratory designed two potent biological constructs called RTL1000 and a second- generation derivative, DRα1-MOG-35-55, that bind tightly to the MIF receptor, CD74, and competitively inhibit MIF binding and downstream signaling through phosphorylated extracellular-related kinase (pERK1/2). RTL1000/DRα1-MOG-35-55 also targets T cell receptors resulting in the inhibition of IL-2 release, T cell and macrophage activation and their migration into the CNS. Treatment of mice with experimental autoimmune encephalomyelitis (EAE – an animal model of MS) with DRα1-MOG-35-55 reduces the severity of both the acute and chronic forms of the disease when administered after onset of clinical signs and also promotes neuroprotection. New findings obtained during the previous Merit Review funding period have established several key facts that provide a solid basis for the studies proposed in this resubmission, including: 1) Detailed understanding of MIF and D-DT molecular interactions with their common receptor, CD74 and their contributions to acute and chronic EAE disease severity; 2) Discovery and characterization of DRQ, an ~8-fold more potent variant of DRα1-MOG-35-55 called DRhQ, [DRα1(L50Q)-human (h)MOG-35-55] for human clinical trials and its homolog, DRmQ, [DRα1(L50Q)-mouse (m)MOG-35-55] that was created for use in rodents; and 3) Demonstration that DRmQ treatment of acute and chronic EAE not only blocks signaling through the MIF/CD74 axis and the T cell receptor, but also inhibits additional proinflammatory pathways and promotes neuroprotection. The hypothesis to be addressed in this renewal application is that DRQ can inhibit inflammatory innate and adaptive immune pathways and simultaneously stimulate remyelination and neuronal protection. The major goals of the current grant application are to evaluate possible proinflammatory interactions between the MIF/CD74 axis with the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway in EAE; and to determine if DRmQ can block TREM-1, CXCR2 (which inhibits oligodendrocyte precursor proliferation) and the TCR and simultaneously enhance three neuroprotective pathways involving TREM-2 and several chemokine ligand and receptor pairs that were implicated in cytokine/chemokine screening studies. This triad spectrum of DRQ inhibition of MIF/CD74, TREM-1 and encephalitogenic T cell activity coupled with its stimulatory effects on CNS remyelination and axonal health in EAE will validate the unique therapeutic potential of DRhQ for MS and allow this novel “designer” drug to compete favorably with current and future monoclonal antibody and other currently approved therapies for MS that are directed at single target molecules.

多发性硬化症 (MS) 是一种破坏性的中枢神经系统慢性脱髓鞘自身免疫性疾病 系统（中枢神经系统）。两种关键的细胞因子/趋化因子被认为可将多发性硬化症的早期炎症阶段转变为慢性。 进展期是巨噬细胞迁移抑制因子 (MIF) 及其同源物 D-多巴色素 我们的实验室设计了两种有效的生物结构，称为 RTL1000 和第二种- 一代衍生物 DRα1-MOG-35-55，与 MIF 受体 CD74 紧密结合，并竞争性抑制 MIF 结合和下游信号传导通过磷酸化细胞外相关激酶 (pERK1/2)。 RTL1000/DRα1-MOG-35-55 还靶向 T 细胞受体，从而抑制 IL-2 释放、T 细胞和 巨噬细胞激活及其迁移至中枢神经系统的实验性自身免疫小鼠的治疗。 DRα1-MOG-35-55 可降低脑脊髓炎（EAE – MS 动物模型）的严重程度 和慢性形式的疾病，当在临床症状出现后施用时，也会促进 神经保护。在上一个优点审查资助期间获得的新发现已经确定。 为本次重新提交中提出的研究提供坚实基础的几个关键事实，包括： 1) 详细 了解 MIF 和 D-DT 分子与其共同受体 CD74 的相互作用及其贡献 急性和慢性 EAE 疾病的严重程度；2) DRQ 的发现和表征，其效力增强约 8 倍 DRα1-MOG-35-55 的变体称为 DRhQ，[DRα1(L50Q)-人 (h)MOG-35-55] 用于人体临床试验及其 同源物，DRmQ，[DRα1(L50Q)-小鼠 (m)MOG-35-55]，用于啮齿动物；3) 演示； DRmQ 治疗急性和慢性 EAE 不仅阻断通过 MIF/CD74 轴和 T 的信号传导 细胞受体，还抑制其他促炎途径并促进神经保护。 本次更新申请中要解决的假设是 DRQ 可以抑制先天性和适应性炎症 免疫途径并同时刺激髓鞘再生和神经保护。 目前的拨款申请是评估 MIF/CD74 轴与 EAE 中骨髓细胞 1 (TREM-1) 通路上表达的触发受体；并确定 DRmQ 是否可以 阻断 TREM-1、CXCR2（抑制少突胶质细胞前体增殖）和 TCR，同时 增强涉及 TREM-2 和多个趋化因子配体和受体对的三个神经保护途径 与细胞因子/趋化因子筛选研究有关的 DRQ 抑制三联谱。 MIF/CD74、TREM-1 和致脑炎 T 细胞活性及其对中枢神经系统髓鞘再生的刺激作用 EAE 中的轴突健康和轴突健康将验证 DRhQ 对 MS 的独特治疗潜力，并允许这种新颖的治疗方法 “设计”药物可与当前和未来的单克隆抗体和其他目前批准的药物进行竞争 针对单一靶分子的多发性硬化症疗法。