Immunoregulation of Myelin Specific T Lymphocytes

描述（由申请人提供）： 多发性硬化症（MS）是一种进行性麻痹性人类脱髓鞘疾病，可由中枢神经系统（CNS）的自身免疫攻击引起或加重。这种攻击在大脑和脊髓中产生严重的炎症，这种炎症由称为T淋巴细胞的白色血细胞介导，T淋巴细胞被编程为识别和破坏髓鞘的成分。我们的实验室设计并开发了一种新的分子家族，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色血细胞的炎症作用。RTL的治疗效果已经在经历实验性自身免疫性脑脊髓炎（EAE）的小鼠中进行了评价，EAE是MS的动物模型，其涉及麻痹性慢性或复发性病程以及对中枢神经系统的髓鞘和神经细胞的进行性损伤。EAE发作后的RTL治疗逆转了麻痹的临床体征，并改变了受损T淋巴细胞的性质，使其成为非致病性的。除了通过T细胞受体（如设计的）直接调节T细胞活化之外，最近发现RTL通过首先与其他血细胞结合，然后向T细胞特异性地“呈现”独特信号来诱导T细胞的变化。此外，RTL治疗显示逆转EAE中的炎症、细胞浸润以及髓鞘和轴突损伤，表明对整个CNS具有神经保护作用。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信号传导事件。为了实现这一目标，提出：1）评估RTL结合来自血液的抗原呈递细胞并诱导使致病性T淋巴细胞无害的变化的过程，和2）在小鼠中评估RTL疗法如何影响血脑屏障以防止炎性细胞进入并因此保护CNS免受髓鞘和神经的T细胞损伤。这项工作对于我们理解RTL疗法如何改变T细胞功能和逆转CNS中的炎症和髓鞘损伤至关重要。这些研究将提供独特的见解和方法来记录RTL治疗在MS受试者中的效果。 公共卫生相关性： 多发性硬化症（MS）是一种进行性麻痹性人类脱髓鞘疾病，可能由中枢神经系统（CNS）的自身免疫攻击引起或加重。T淋巴细胞活化（白色血细胞的一种亚型）与髓鞘肽的特异性受体可导致MS受试者的脑和脊髓中的髓鞘和神经的炎症和严重损伤。可逆转临床和组织学损伤，促进临床改善和脊髓中髓鞘和神经的再生。RTL逆转MS样疾病进展的能力表明，这种药物可能对治疗MS受试者非常有效，包括在全国VA医院接受治疗的退伍军人。基于这些和其他已获得专利和发表的临床前数据，Artielle ImmunoTherapeutics Inc（该公司拥有VA和OHSU关于RTL平台技术的全球独家许可）已获得IND #100128“RTL 1000“重组T细胞受体配体”该研究招募了5个队列，每个队列中有6名MS受试者，4名接受药物，2名接受安慰剂。每个随后的组群接受静脉内给予的增加剂量的RTL 1000，从单次注射的最低剂量2 mg开始（起始剂量由先前MR授权的临床前研究确定），并逐步增加至6，20，60和200 mg。在撰写本文时（2008年8月），队列1、2和3已完成，无安全性问题，队列4处于中途，无明显安全性问题。关于这项试验的更多信息可以在clinicaltrials.gov（在“多发性硬化症”中键入）或国家多发性硬化症网站上的MS当前临床试验下查看。这项研究代表了VA资助的研究直接转化为人类临床研究，可能直接应用于MS退伍军人。

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.