Immunomodulation and Neuroprotection in Multiple Sclerosis

多发性硬化症的免疫调节和神经保护

• 批准号: 9920592
• 负责人: Inderjit Singh
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920592
• 关键词: Affect; Amino Acids; Animal Model; Animals; Anti-Inflammatory Agents; Arginine; Autoimmune Diseases; Autoimmune Responses; Biological; Blood; Blood - brain barrier anatomy; Blood Vessels; Catabolism; Central Nervous System Diseases; Clinical; Clinical Pathology; Development; Disease; Disease Marker; Disease Progression; Drug Targeting; Endothelial Cells; Endothelium; Experimental Autoimmune Encephalomyelitis; FDA approved; Folic Acid; Functional disorder; Goals; Health; Homeostasis; Homocysteine; Immune; Immune System Diseases; Immune Targeting; Immune response; Immune system; Immunologics; Immunosuppression; Immunotherapy; Impairment; Individual; Infiltration; Inflammatory; Laboratories; Lead; Lymphocyte; Maintenance; Mediating; Metabolism; Mission; Modeling; Multiple Sclerosis; Mus; Myelin; N,N-dimethylarginine; Neurologic; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthetase Inhibitor; Pathogenesis; Pathologic; Pathology; Peripheral; Peroxonitrite; Pertussis Toxin; Pharmaceutical Preparations; Physiological; Play; Process; Production; Regulation; Regulatory T-Lymphocyte; Reporting; Role; S-Nitrosoglutathione; Safety; Severity of illness; Signal Transduction; Sulfhydryl Compounds; Superoxides; System; T-Lymphocyte; Testing; Therapeutic; Time; Vascular Diseases; Veterans; Vitamin B 12; attenuation; autoreactivity; base; brain endothelial cell; clinically relevant; dimethylargininase; immunoregulation; improved; inhibitor/antagonist; insight; interest; mouse model; multiple sclerosis patient; nervous system disorder; neurological pathology; neuroprotection; novel; novel therapeutics; prognostic; targeted treatment; therapeutic target

Multiple sclerosis (MS), a disabling autoimmune disease affecting almost 2.5 million people around the world, affects individuals in their most productive years and is prevalent among US Veterans. MS is caused by abnormal activation of myelin-specific autoreactive lymphocytes and their CNS infiltration across the blood- brain barrier (BBB). Present day FDA approved MS drugs, targeting immune system, have limited efficacies as disease progression continues. In an effort to improve MS therapy, the goal of this proposal is to evaluate the feasibility of nitric oxide synthase (NOS) and nitric oxide (NO) metabolites as potential therapeutic target(s) for immune as well as BBB pathogenesis, two critical disease mechanisms of MS. Recent studies from our laboratory and others have documented the roles of NOS and NO metabolites (S- nitrosoglutathione; GSNO vs. peroxynitrite; ONOO¯) in physiological vs. pathological regulation of experimental autoimmune encephalomyelitis (EAE; a model for MS). Asymmetric dimethylarginine (ADMA), a cellular metabolite of L-arginine, shifts the NOS activity from NO production to superoxide (O2·¯) production, thus leading to increased toxic ONOO¯ formation. Therefore, elevation of ADMA levels in EAE and MS could potentially shift the NOS activity for increased production of ONOO¯ and thus cause related severe pathologies. The pathological importance of ADMA in MS was recognized first by the reported elevation of blood ADMA in MS patients. Next, our studies document the elevated blood ADMA in EAE. We further observed that treatment of EAE animals with exogenous ADMA aggravates the disease severity by increasing TH1/TH17 mediated pro- inflammatory immune responses. In addition, ADMA induced ONOO¯ synthesis in the brain microvascular endothelial cells and caused BBB dysfunction/disruption for CNS infiltration of immunocytes even in the absence of pertussis toxin. These findings, for the first time, document the participation of ADMA-mediated mechanisms in immune pathogenesis as well as BBB dysfunction in EAE. Our laboratory previously reported that NO and its physiological carrier molecule GSNO play critical roles in autoimmune responses as well as in maintenance of endothelial barrier integrity in EAE. These observations lead us to hypothesize that elevation of ADMA as a result of its defective metabolism, during the course of EAE, induces NOS dysfunction leading to inhibition of NO/GSNO-mediated anti-inflammatory and vaso-protective activity, while inducing the O2·¯/ONOO¯- mediated pro-inflammatory and vaso-disruptive activity in EAE. Therefore, ADMA-mediated mechanisms are novel and a potential therapeutic target for immune and BBB pathogenesis of MS/EAE. Based on this hypothesis, the proposed studies are to investigate the temporal relationship between dysfunctional ADMA and NO (ONOO¯ vs. GSNO) metabolism and immunological, vascular, neurological, and clinical pathologies of EAE (AIM 1), mechanism underlying impaired ADMA catabolism by DDAH-1/2 in EAE (AIM 2) and to evaluate potential therapeutics targeting ADMA and NO metabolism in EAE (AIM 3). The proposed studies are based on our original findings of pathological significance of ADMA in NOS/NO- mediated immune and vascular disease mechanisms of EAE. Results from these studies are expected to provide novel insights into disease mechanisms and to identify novel potential targets and therapeutics for MS. Translational potential of this study is high as GSNO mediated mechanisms target immune modulation (TH1/TH17 < TH2/Treg), rather than global immune suppression, as well as BBB pathologies of EAE.

多发性硬化症（MS），一种残疾自身免疫性疾病，影响了近250万人 世界，影响个人最有生产力的年龄，在美国退伍军人中普遍存在。 MS是引起的 通过异常激活髓磷脂特异性自身反应性淋巴细胞及其中枢神经系统渗透到血液中 脑屏障（BBB）。当今FDA批准的MS药物，靶向免疫系统的效率有限 随着疾病进展的继续。为了改善MS治疗，该建议的目的是评估 一氧化氮合酶（NOS）和一氧化氮（NO）代谢物的可行性作为潜在的治疗靶标 对于免疫和BBB发病机理，MS的两种关键疾病机制。 我们实验室和其他人的最新研究记录了NOS和没有代谢物的作用（S- 硝酸硫酸硫酸盐； GSNO vs.过氧亚硝酸盐；在生理学和实验的病理调节中） 自身免疫性脑脊髓炎（EAE； MS的模型）。不对称二甲基金融氨酸（ADMA），一种细胞 L-精氨酸的代谢产物将NOS活性从NO生产转移到超氧化物（O2·）生产，因此领先 增加毒性的形成。因此，EAE和MS中ADMA水平的升高可能会改变 NOS活性增加了Onoo的产生，因此引起了相关的严重病理。 据报道 MS患者。接下来，我们的研究记录了EAE的血液ADMA升高。我们进一步观察到治疗 外源性ADMA的EAE动物通过增加Th1/Th17介导的促进性来加剧疾病的严重程度 炎症免疫反应。此外，ADMA诱导脑微血管中的Onoo合成 内皮细胞并引起BBB功能障碍/中枢神经系统渗透免疫细胞的功能障碍/破坏 缺乏百日咳毒素。这些发现首次记录了ADMA介导的参与 EAE免疫发病机理以及BBB功能障碍的机制。我们的实验室以前报道了 No及其物理载体分子GSNO在自身免疫反应中起着至关重要的作用 维持EAE内皮屏障完整性。这些观察结果使我们假设 ADMA由于其有缺陷的代谢而导致EAE过程中引起了NOS功能障碍，导致 抑制NO/GSNO介导的抗炎和血管保护活性，同时诱导O2·/Onoo-- EAE中介导的促炎和血管干扰活性。因此，ADMA介导的机制是 MS/EAE的免疫和BBB发病机理的新颖和潜在的治疗靶标。基于这个假设， 拟议的研究是研究功能失调的ADMA与NO之间的临时关系 （Onoo vs. GSNO）代谢和免疫学，血管，神经和临床病理学 EAE（AI​​M 1），DDAH-1/2在EAE中的ADMA分解代谢受损的机制（AIM 2）和to 评估靶向ADMA的潜在治疗剂，而在EAE中无代谢（AIM 3）。 拟议的研究基于我们最初对ADMA在NOS/NO-的病理意义的发现 EAE的介导的免疫和血管疾病机制。这些研究的结果有望提供 对疾病机制的新见解，并确定了MS的新型潜在靶标和治疗。 由于GSNO介导的机制靶向免疫调节，这项研究的翻译潜力很高 （Th1/Th17 <Th2/Treg），而不是全球免疫抑制，以及EAE的BBB病理。