Protection against acute inflammatory demyelinating peripheral nerve disease

预防急性炎症性脱髓鞘性周围神经疾病

• 批准号: 7626829
• 负责人: Evan B. Stubbs
• 金额: $ 5.95万
• 依托单位: CHICAGO ASSN FOR RESEARCH & EDUC IN SCI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626829
• 关键词: Activated Lymphocyte; Acute; Address; Adjuvant; Advanced Development; Affect; American; Animal Model; Animals; Annual Reports; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Asia; Attenuated; Autoantigens; Autoimmune Diseases; Autoimmune Process; Axonal Neuropathy; Blood-Nerve Barrier; C-reactive protein; Caring; Case Study; Cattle; Cell Adhesion Molecules; Cell surface; Cells; Cellular Immunity; China; Clinical; Coenzyme A; Country; Demyelinations; Development; Disease; Dose; E-Selectin; Economic Burden; Economics; Emulsions; Endothelial Cells; Epitopes; Etiology; Europe; European; Event; Experimental Autoimmune Neuritis; Frequencies; Glycoproteins; Goals; Guillain-Barré Syndrome; Harvest; Histocompatibility Antigens Class II; Home environment; Immune; Immune system; Immunization; Immunohistochemistry; In Vitro; Incidence; Individual; Infiltration; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Laboratory Animals; Leukocyte Trafficking; Leukocytes; Lovastatin; Measures; Mechanical ventilation; Mediating; Miller Fisher Syndrome; Modeling; Monoclonal Antibodies; Motor; Multiple Sclerosis; Muscle Weakness; Myelin; Myelin Proteins; Myelin Sheath; Nerve; Neuropathy; North America; Oxidoreductase; Paralysed; Paresis; Pathogenesis; Pathogenicity; Pathologic; Patients; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Peripheral nerve injury; Poliomyelitis; Polyradiculopathy; Process; Production; Rattus; Reporting; Research Proposals; Respiratory Failure; Reverse Transcriptase Polymerase Chain Reaction; Sensory; Signal Transduction; Simvastatin; Social Impacts; Syndrome; T-Cell Activation; T-Lymphocyte; Taiwan; Testing; Therapeutic; Time; Vascular Cell Adhesion Molecule-1; Western Blotting; autoreactive T cell; chemokine; cytokine; in vivo; inflammatory marker; inhibitor/antagonist; lymphocyte proliferation; mRNA Expression; migration; neuromuscular; novel; novel strategies; palliative; public health relevance; response; rho GTP-Binding Proteins; sciatic nerve; social; treatment strategy; virtual

DESCRIPTION (provided by applicant): Acute inflammatory demyelinating polyradiculopathy (AIDP) is a common North American and European form of Guillain-Barre' Syndrome (GBS), a disabling inflammatory autoimmune disease of the peripheral nervous system that is characterized by rapid-onset symmetrical paresis with areflexia progressing to neuromuscular paralysis. Considered the leading cause of acute flaccid paralysis in Western countries, GBS occurs with an incidence rate of 0.2-4.0 cases per 100,000. Despite its considerable social impact and economic consequences, studies addressing clinical strategies for the treatment of GBS remain poorly represented. Enhanced infiltration of inflammatory cells into peripheral nerves of GBS patients is strongly suggestive of an immune-mediated pathogenic process. Cellular immunity directed against specific constituents of the peripheral nerve myelin sheath is considered causal in AIDP. The treatment of AIDP/GBS is currently palliative and utilizes non-specific immune-modulating therapies. Advancement of care for GBS patients awaits the development of selective immune-modulating agents or the novel application of existing therapeutic strategies. To address this concern, we recently reported on the application of statins, a group of potent 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, as a novel strategy for the management of experimental autoimmune neuritis (EAN), a well-defined animal model of acute inflammatory peripheral nerve disease. We found that a short-term application of lovastatin was non-toxic and protected against EAN-induced peripheral nerve injury by inhibiting the transendothelial migration of autoreactive leukocytes. How statins affect the migration of autoreactive leukocytes is unclear. In this application, we hypothesize that statins protect against the development of EAN by inhibiting Rho GTPase dependent expression of key cell adhesion molecules on peripheral nerve endothelial cells. We will test this hypothesis using the following Specific Aims: We will determine (1) the dose- and time-dependent effect of lovastatin and simvastatin treatment on Rho-GTPase dependent expression of E-selectin, ICAM-1 and VCAM-1 in primary cultures of rat sciatic nerve endothelial cells and (2) the effect of lovastatin and simvastatin treatment on cell-specific expression of E-selectin, ICAM-1 and VCAM-1 in sciatic nerves harvested from vehicle- or statin-treated Lewis rats with EAN. The overall goal of this application is to define the mechanism by which statins protect against the development of autoimmune inflammatory demyelinating polyradiculopathy. We argue that findings from this study will significantly advance the development of statins as a selective immune-modulating strategy for the treatment of those individuals affected by GBS and related debilitating inflammatory peripheral nerve diseases. PUBLIC HEALTH RELEVANCE Guillain-Barre' Syndrome (GBS) is a potentially highly disabling acquired inflammatory autoimmune disease of the peripheral nervous system that is characterized by a rapid-onset of muscle weakness that in some patients progresses to respiratory failure and paralysis. Subsequent to the virtual eradication of poliomyelitis, GBS is now considered the leading cause of acute flaccid paralysis in Western countries (1) with a reported annual stable incidence rate of 0.2-4.0 cases per 100,000 (2; 3), a rate that is surprisingly similar to that reported for multiple sclerosis (1; 4). In the US, nearly 10,000 GBS cases are reported annually with an overall yearly social and economic burden exceeding $1.8 billion (5). Despite its considerable social impact and economic consequences, studies addressing clinical strategies for the treatment of GBS remain poorly represented. The overall goal of this application is to define the mechanism by which statins protect against the development of autoimmune inflammatory demyelinating polyradiculopathy. We argue that findings from this study will significantly advance the development of statins as a selective immune-modulating strategy for the treatment of those individuals affected by GBS and related debilitating inflammatory peripheral nerve diseases.

描述（由申请人提供）：急性炎性脱髓鞘性多神经根病（AIDP）是格林-巴利综合征（GBS）的一种常见北美和欧洲形式，GBS是一种周围神经系统的致残性炎性自身免疫性疾病，其特征为快速发作的对称性轻瘫伴反射消失进展为神经肌肉麻痹。在西方国家，GBS被认为是急性弛缓性麻痹的主要原因，发病率为每10万人0.2-4.0例。尽管其相当大的社会影响和经济后果，研究解决GBS治疗的临床策略仍然代表性不足。GBS患者外周神经炎性细胞浸润增强强烈提示免疫介导的致病过程。针对周围神经髓鞘特定成分的细胞免疫被认为是AIDP的病因。AIDP/GBS的治疗目前是姑息性的，并利用非特异性免疫调节疗法。GBS患者护理的进步等待选择性免疫调节剂的开发或现有治疗策略的新应用。为了解决这一问题，我们最近报道了他汀类药物的应用，一组有效的3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂，作为一种新的策略，用于管理实验性自身免疫性神经炎（EAN），一个明确的急性炎症性周围神经疾病的动物模型。我们发现，短期应用洛伐他汀是无毒的，并通过抑制自身反应性白细胞的跨内皮迁移来保护EAN诱导的周围神经损伤。他汀类药物如何影响自身反应性白细胞的迁移尚不清楚。在本申请中，我们假设他汀类药物通过抑制外周神经内皮细胞上关键细胞粘附分子的Rho GT3依赖性表达来预防EAN的发展。我们将使用以下具体目标来检验这一假设：我们将确定（1）洛伐他汀和辛伐他汀处理对大鼠坐骨神经内皮细胞原代培养物中E-选择素、ICAM-1和VCAM-1的Rho-GT依赖性表达的剂量和时间依赖性作用，以及（2）洛伐他汀和辛伐他汀处理对E-选择素的细胞特异性表达的作用，从溶剂或他汀类药物治疗的EAN刘易斯大鼠中收获的坐骨神经中的ICAM-1和VCAM-1。本申请的总体目标是确定他汀类药物预防自身免疫性炎性脱髓鞘性多发性神经根病发展的机制。我们认为，这项研究的结果将显着推进他汀类药物作为一种选择性免疫调节策略，用于治疗受GBS和相关的衰弱性炎症性周围神经疾病影响的个体的发展。格林-巴利综合征（GBS）是一种潜在的高度致残的外周神经系统获得性炎性自身免疫性疾病，其特征在于肌肉无力的快速发作，在一些患者中进展为呼吸衰竭和瘫痪。在脊髓灰质炎基本根除后，GBS现在被认为是西方国家急性弛缓性麻痹的主要原因（1），报告的年稳定发病率为0.2-4.0例/100，000（2; 3），该发病率与多发性硬化症报告的发病率惊人地相似（1; 4）。在美国，每年报告近10，000例GBS病例，总体年度社会和经济负担超过18亿美元（5）。尽管其相当大的社会影响和经济后果，研究解决GBS治疗的临床策略仍然代表性不足。本申请的总体目标是确定他汀类药物预防自身免疫性炎性脱髓鞘性多发性神经根病发展的机制。我们认为，这项研究的结果将显着推进他汀类药物作为一种选择性免疫调节策略，用于治疗受GBS和相关的衰弱性炎症性周围神经疾病影响的个体的发展。

项目成果

Cdc42 GTPases facilitate TNF-α-mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells.

• DOI: 10.1111/jns5.12032
• 发表时间: 2013-09
• 期刊: Journal of the peripheral nervous system : JPNS
• 作者: Langert KA;Von Zee CL;Stubbs EB Jr
• 通讯作者: Stubbs EB Jr

Tumour necrosis factor α enhances CCL2 and ICAM-1 expression in peripheral nerve microvascular endoneurial endothelial cells.

• DOI: 10.1042/an20120048
• 发表时间: 2013-02-06
• 期刊: ASN neuro
• 影响因子: 4.7
• 作者: Langert KA;Von Zee CL;Stubbs EB Jr
• 通讯作者: Stubbs EB Jr