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: 10455525
• 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/10455525
• 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; Persons; 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; disease prognostic; immunoregulation; improved; inhibitor; insight; interest; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nervous system disorder; neurological pathology; neuroprotection; novel; novel therapeutics; targeted treatment; therapeutic target; translational potential

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）是一种致残性自身免疫性疾病，影响着全球近250万人。 世界上，影响个人在他们最富有成效的几年，是普遍的美国退伍军人。MS是由 髓鞘特异性自身反应性淋巴细胞的异常激活及其穿过血液的CNS浸润- 脑屏障（BBB）。目前FDA批准的针对免疫系统的MS药物疗效有限 随着疾病的持续进展。为了改善MS治疗，本提案的目标是评估 一氧化氮合酶（NOS）和一氧化氮（NO）代谢物作为潜在治疗靶点的可行性 免疫和血脑屏障的发病机制，两个关键的疾病机制的MS。 我们实验室和其他实验室最近的研究已经证明了NOS和NO代谢物（S- 亚硝基谷胱甘肽; GSNO vs.过氧亚硝酸盐; ONOO <$）在实验性肝纤维化的生理与病理调节中的作用 自身免疫性脑脊髓炎（EAE; MS的模型）。不对称二甲基精氨酸（ADMA）， L-精氨酸的代谢产物，将NOS活性从NO产生转移到超氧化物（O2·<$）产生，从而导致 增加有毒ONOO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ONOO ′的产生，从而引起相关的严重病理。 ADMA在MS中的病理学重要性首先通过在MS患者中报告的血ADMA升高而被认识到。 MS患者接下来，我们的研究记录了EAE中血液ADMA的升高。我们进一步观察到， 外源性ADMA的EAE动物通过增加TH 1/TH 17介导的促肾上腺皮质激素释放激素（Pro-1）， 炎症免疫反应。此外，ADMA诱导脑微血管中ONOO <$合成， 内皮细胞和引起的BBB功能障碍/破坏的CNS浸润的免疫细胞，即使在 没有百日咳毒素。这些发现首次记录了ADMA介导的 EAE的免疫发病机制以及BBB功能障碍。我们的实验室先前报告说 NO及其生理载体分子GSNO在自身免疫反应中起着关键作用， EAE中内皮屏障完整性的维持。这些观察使我们假设， ADMA由于其代谢缺陷，在EAE过程中诱导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 <$- 介导的促炎和血管破坏活性。因此，ADMA介导的机制是 为MS/EAE的免疫和BBB发病机制提供了新的和潜在的治疗靶点。基于这一假设， 拟开展的研究旨在探讨功能失调的ADMA与NO之间的时间关系， (ONOO与GSNO）代谢和免疫学、血管、神经学和临床病理学 EAE（AIM 1），EAE（AIM 2）中DDAH-1/2受损ADMA催化的潜在机制， 评估针对EAE（AIM 3）中ADMA和NO代谢的潜在疗法。 这些研究是基于我们最初发现的ADMA在NOS/NO- 介导的免疫和血管疾病机制。这些研究的结果预计将提供 对疾病机制的新见解，并确定MS的新的潜在靶点和治疗方法。 本研究的转化潜力很高，因为GSNO介导的机制靶向免疫调节 (TH1/TH 17 <TH 2/Treg），而不是整体免疫抑制，以及EAE的BBB病理学。