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: 8198384
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198384
• 关键词: Address; Affect; Aftercare; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Process; B-Lymphocytes; Binding; Blood; Blood - brain barrier anatomy; Blood Cells; Brain; CD28 gene; Cell physiology; Cell surface; Cells; Cellular Infiltration; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Data; Clinical Research; Clinical Trials; Complex; Demyelinating Diseases; Demyelinations; Dendritic Cells; Disease; Dose; Enrollment; Event; Experimental Autoimmune Encephalomyelitis; Experimental Models; Family; Foundations; Funding; Goals; Grant; HLA-DR2 Antigen; Hospitals; Human; Immigration; Immune response; Immunotherapeutic agent; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Knock-in Mouse; Knock-out; Laboratories; Legal patent; Leukocytes; Licensing; Ligand Binding; Ligands; Ligation; Link; MHC Class II Genes; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Myelin; Myelin Proteolipid Protein; Myelin Sheath; Natural regeneration; Nerve; Neuraxis; Neurons; Organ; Paralysed; Pathway interactions; Pattern; Peptide/MHC Complex; Peptides; Pharmaceutical Preparations; Phase; Phenotype; Phosphorylation; Phosphotransferases; Placebos; Process; Property; Publishing; Recombinants; Recurrent disease; Relapse; Research; Resistance; Safety; Secondary to; Signal Transduction; Spinal Cord; Surface Antigens; T cell regulation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic Effect; Translations; Vascular Endothelial Cell; Veterans; Work; Writing; abstracting; base; cell injury; cohort; cytokine; design; direct application; immunoregulation; insight; macrophage; neuroprotection; novel; pre-clinical; preclinical study; prevent; programs; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; safety study; web site

DESCRIPTION (provided by applicant): Project Summary/Abstract Multiple sclerosis (MS) is a progressive paralytic human demyelinating disease may be caused or made worse due by an autoimmune attack on the central nervous system (CNS). This attack produces severe inflammation in the brain and spinal cord that is mediated by white blood cells, called T lymphocytes, which are programmed to recognize and damage components of the myelin sheath. Our laboratory has designed and developed a novel family of molecules, called RTLs (Recombinant T cell receptor Ligands), that can selectively block the inflammatory effects of these damaging white blood cells. Therapeutic effects of RTL have been evaluated in mice undergoing Experimental Autoimmune Encephalomyelitis (EAE), an animal model for MS that involves a paralytic chronic or relapsing disease course and progressive damage to myelin and nerve cells of the central nervous system. RTL treatment after onset of EAE reversed paralytic clinical signs and changed the properties of the damaging T lymphocytes to become non-pathogenic. In addition to direct modulation of T cell activation through the T cell receptor (as designed), RTLs were recently discovered to induce changes in the T cells by first binding to other blood cells that then "present" unique signals specifically to the T cells. Additionally, RTL therapy was shown to reverse inflammation, cellular infiltration and myelin and axonal damage in EAE, suggesting a neuroprotective effect on the entire CNS. The overall goal of this proposal is to characterize the RTL signaling events that cause these critical changes in the pathogenic T cells. To address this goal, it is proposed to: 1) evaluate the process through which RTLs bind to antigen presenting cells from blood and induce changes that render the pathogenic T lymphocytes harmless, and 2) evaluate in mice how RTL therapy can affect the blood brain barrier in order to prevent entry of inflammatory cells and thus protect the CNS from T cell damage to myelin and nerves. The work proposed is crucial to our understanding of how RTL therapy changes T cell functions and reverses inflammation and myelin damage in CNS. These studies will provide unique insights and approaches to document effects of RTL therapy in subjects with MS. PUBLIC HEALTH RELEVANCE: Project Narrative Multiple sclerosis (MS) is a progressive paralytic human demyelinating disease may be caused or made worse due by an autoimmune attack on the central nervous system (CNS). Activation of T lymphocytes (a subtype of white blood cell) with specific receptors for myelin peptides can result in inflammation and severe damage to myelin and nerves in the brain and spinal cord of subjects with MS. Our studies in an experimental model of MS have demonstrated that treatment of paralyzed mice with a novel drug (RTL) can reverse clinical and histological damage and promote clinical improvement and regeneration of myelin and nerves in the spinal cord. The ability of RTL to reverse progression of the MS-like disease suggested that this drug might be highly effective for treating subjects with MS, including Veterans being treated in VA Hospitals nationwide. Based on these and other pre-clinical data that were patented and published, Artielle ImmunoTherapeutics, Inc (the company that has a worldwide exclusive license from VA and OHSU for the RTL platform technology) has obtained an IND#100128 "RTL1000 "Recombinant T Cell Receptor Ligand" from FDA and has initiated a human Phase 1 safety study for use of RTL1000 in subjects with MS. The study is enrolling 5 cohorts of 6 MS subjects, 4 receiving drug and 2 receiving placebo in each cohort. Each succeeding cohort receives an increasing dose of RTL1000 given i.v., starting with the lowest dose of 2mg given as a single injection (starting dose determined by preclinical studies from the previous MR grant), and escalating to 6, 20, 60, and 200mg. At this writing (August, 2008), cohorts 1, 2 and 3 have been completed without safety issues, and cohort 4 is midway without apparent safety concerns. Further information on this trial can be viewed at clinicaltrials.gov (key in "Multiple Sclerosis") or on the National Multiple Sclerosis website under current clinical trials in MS. This study represents a direct translation of VA funded research into a human clinical study that may have direct application to Veterans with MS.

描述（由申请人提供）： 项目摘要/摘要多发性硬化症（MS）是一种进行性瘫痪的人性化脱髓鞘疾病，可能是由于对中枢神经系统（CNS）的自身免疫性攻击而导致的或更严重的。这种攻击会在大脑和脊髓中产生严重的炎症，脊髓被白细胞介导，称为T淋巴细胞，这些淋巴细胞被编程为识别和损害髓鞘鞘的成分。我们的实验室设计并开发了一种新型的分子家族，称为RTL（重组T细胞受体配体），可以选择性地阻断这些破坏性白细胞的炎症作用。在接受实验性自身免疫性脑脊髓炎（EAE）的小鼠中，已经评估了RTL的治疗作用，这是MS的动物模型，其中涉及麻痹性慢性或复发性疾病病程以及对中枢神经系统的髓鞘和神经细胞的逐渐损害。 EAE发作后的RTL处理逆转了麻痹临床体征，并将破坏性T淋巴细胞的特性更改为非致病性。除了通过T细胞受体直接调节T细胞激活（如设计）外，最近发现RTL通过首先与其他血细胞结合，从而诱导T细胞的变化，该血细胞与其他血细胞结合，然后与其他血液细胞结合，然后“呈现”专门针对T细胞的独特信号。此外，RTL疗法显示出EAE中的炎症，细胞浸润以及髓磷脂和轴突损伤，这表明对整个CNS产生神经保护作用。该提案的总体目标是表征导致致病性T细胞中这些关键变化的RTL信号事件。为了解决这一目标，提议：1）评估RTL与血液中呈现细胞的抗原结合并诱导致病性T淋巴细胞的变化的过程，以及2）2）评估RTL疗法如何影响血液脑屏障，以防止炎症细胞进入炎症细胞，从而从细胞中损害CNS和CNS损害CNS的神经和神经，并损害CNS的神经，并损害了CNS的神经。提出的工作对于我们对RTL治疗如何改变T细胞功能并逆转CNS炎症和髓磷脂损伤至关重要。这些研究将提供独特的见解和方法来记录MS受试者RTL治疗的影响。 公共卫生相关性： 项目叙事多发性硬化症（MS）是一种进行性瘫痪的人性化脱髓鞘疾病，可能是由于对中枢神经系统（CNS）的自身免疫性攻击而导致的。用特定受体的髓磷脂肽的特定受体的T淋巴细胞（白细胞亚型）激活会导致炎症，并严重损害具有MS的大脑和受试者的脑和脊髓的骨髓和神经。我们在MS实验模型中的研究表明，用新型药物（RTL）治疗瘫痪的小鼠可以逆转临床和组织学损害，并促进脊髓中髓磷脂和神经的临床改善和再生。 RTL逆转MS样疾病进展的能力表明，该药物可能非常有效地治疗MS的受试者，包括在全国VA医院接受治疗的退伍军人。基于这些也获得专利和发布的临床前数据，Artielle Immunaphapeutics，Inc（该公司拥有VA和OHSU的全球独家许可，用于RTL平台技术）已获得了IND＃100128“ RTL1000” RTL1000“ RTL1000”重组T细胞受体研究，并在FDA中使用了MSSEAPER in MSESS SAIFESS的SAIFESS IS IS SAIFESS IS SAIFESS IS SAIFESS IS SAIFESS IS。在每个队列中，有5个受试者的5个受试者，4个接受安慰剂。从静脉注射的每个队列中，升高的RTL1000剂量越来越多，从单个注射剂给出的2mg的剂量为2mg（由先前的MR Grant中的急流研究决定） 2和3的完成没有安全问题，并且在临床中，同时4个在没有明显的安全问题的情况下，在此试验中进行了明显的安全问题。这项研究代表了VA资助的研究直接翻译为人类临床研究，该研究可能直接应用于MS的退伍军人。