Oligodendrocyte extracellular vesicles: a novel therapy for CNS autoimmunity

少突胶质细胞外囊泡：中枢神经系统自身免疫的新疗法

• 批准号: 10115612
• 负责人: A.M. Rostami
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10115612
• 关键词: Address; Animal Model; Animals; Antigen Targeting; Antigens; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; CNS autoimmunity; Cell Line; Cells; Chronic; Clinical; Data; Development; Disease; Epitope spreading; Epitopes; Evolution; Experimental Animal Model; Experimental Autoimmune Encephalomyelitis; Failure; Flare; Genetic; Goals; Heterogeneity; Human; Immune Targeting; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunosuppression; Injections; Interferon Type II; Interferons; Interleukin-10; Intravenous; Knockout Mice; Knowledge; Mediating; Modeling; Multiple Sclerosis; Mus; Myelin; Myelin Proteins; Nose; Oligodendroglia; Oral; Pathogenesis; Pathogenicity; Patients; Peptides; Peripheral; Production; Research; Rest; Role; Route; Serious Adverse Event; Specificity; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Translations; Treatment Efficacy; Uncertainty; base; clinically relevant; conditional knockout; extracellular vesicles; humanized mouse; immune system function; immunoregulation; in vivo; multiple sclerosis patient; neuroinflammation; novel therapeutics; particle; peripheral tolerance; programmed cell death ligand 1; prophylactic; reconstitution; response; side effect; success; vesicular release

SUMMARY: Oligodendrocyte extracellular vesicles: a novel therapy for CNS autoimmunity. Current therapies for multiple sclerosis (MS) target the immune system in an antigen (Ag)-nonspecific manner, with potentialy serious side effects due to systemic immunosuppression. A longstanding goal in MS research is to devise an Ag-specific therapy that would suppress only harmful immune responses, while leaving the rest of the immune system intact. The prerequisite for Ag-specific therapy is identification of the target Ag. MS pathogenesis is widely believed to be driven by autoimmunity against myelin Ags. However, the relevant Ag(s) in MS remains speculative, with the possibility that these Ags differ among patients, and over time in the same patient. Numerous approaches for Ag-specific suppression of autoimmune neuroinflammation have been proven in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. These approaches rely on re- establishing peripheral tolerance for self-Ag by delivering the same self-Ag in a non-inflammatory context (eg. in PBS) via various routes, such as intravenous (i.v.), oral, or nasal. However, translation of these experimental strategies into MS therapy has been hampered by uncertainty about the relevant Ags in MS patients. In addressing this issue, we reasoned that if for tolerance induction we used oligodendrocyte (Ol)-derived extracellular vesicles (Ol-EVs), which naturally contain most or all of the myelin Ags, it would be unnecessary to identify the relevant myelin Ag(s) in each patient. Further, we also posited that i.v. injection of Ol-EVs will suppress EAE, similar to well-documented i.v. tolerance induction by free self-peptide. Indeed, our data show that Ol-EVs contained all the relevant myelin Ags and upon i.v. injection ameliorated ongoing EAE in an Ag- dependent manner, suggesting that Ol-EVs can be a universal therapeutic agent for MS. Based on these and additional preliminary data, we hypothesize that human and mouse Ol-EVs contain all relevant myelin Ags, and upon i.v. administration will ameliorate EAE induced by various myelin Ags. We additionally hypothesize that this effect is Ag-dependent and mediated by the IFN-/IL-27/PD-L1 axis. This hypothesis will be tested in the following specific aims: Aim 1. To determine the therapeutic efficacy of Ol-EVs in several EAE models. Since the significance of this project is to study Ol-EVs as a potential therapy for MS, and we do not know the relevant Ag(s) in MS, we will test the hypothesis that OL-EVs/i.v. can suppress EAE induced by any myelin Ag, because all the relevant Ags are present in OL-EVs. Aim 2. To define the mechanism of EAE suppression by Ol-EVs. Our preliminary data provide a basis for the hypothesis that Ol-EVs/i.v. induce tolerogenic APCs, which diminish pathogenic Th cell response and suppress EAE via expression of immunoregulatory molecules. Aim 3. To study the effects of human Ol-EVs in human myelin Ag-induced EAE, and in humanized mice. We will optimize production of human Ol-EVs, and test the hypothesis that human Ol-EVs/i.v. have adequate therapeutic efficacy in EAE models, and in humanized mice to determine if findings in mice are paralleled in this human-like system.

摘要：少突胶质细胞外蔬菜：一种新型CNS自身免疫性的疗法。 多发性硬化症（MS）的当前疗法以抗原（AG）非特异性方式靶向免疫系统 由于全身免疫抑制，潜在的严重副作用。 MS研究中的一个长期目标是 设计一种AG特异性疗法，该疗法只能抑制有害的免疫反应，同时离开其余部分 免疫系统完整。 Ag特异性治疗的先决条件是鉴定靶AG。多发性硬化症 广泛认为发病机理是由对髓磷脂AG的自身免疫性驱动的。但是，相关的ag 在MS中，仍然是投机性的，并且这些AG在患者之间有所不同，并且随着时间的流逝 病人。已证明了许多用于自身免疫性神经炎症的Ag特异性抑制方法 在实验性自身免疫性脑脊髓炎（EAE）中，MS动物模型。这些方法取决于重新 通过在非炎症环境中提供相同的自我来建立对自我的外围耐受性（例如 PBS）通过各种路线，例如静脉内（i.v.），口服或鼻腔。但是，这些实验的翻译 MS治疗的策略受到MS患者相关AG的不确定性的阻碍。在 在解决这个问题时，我们认为，如果耐受性诱导，我们使用了少突胶细胞（OL）衍生的 细胞外蔬菜（OL-EVS）自然包含大多数或全部髓磷脂AG，这是不必要的 确定每个患者中相关的髓磷脂Ag。此外，我们还认为i.v.注射OL-EVS将 抑制EAE，类似于有据可查的I.V.游离自肽诱导耐受性。确实，我们的数据显示 OL-EVS包含所有相关的髓磷脂AG和I.V.注射在Ag中改善正在进行的EAE 依赖方式，表明OL-EV可以是MS的通用治疗剂。基于这些 其他初步数据，我们假设人和小鼠OL-evs包含所有相关的髓磷脂Ags，并且 在I.V.给药将改善各种髓磷脂AG诱导的EAE。我们还假设这是 效应依赖于Ag，并由IFN-/IL-27/PD-L1轴介导。该假设将在以下检验 具体目的：目标1。确定多种EAE模型中OL-EV的治疗效率。自从 该项目的意义是将OL-EV作为MS的潜在疗法研究，我们不知道相关 在MS中，我们将检验OL-EVS/I.V的假设。可以抑制任何髓磷脂Ag引起的EAE，因为 所有相关的AG都存在于OL-EV中。目标2。定义OL-EVS抑制EAE的机制。 我们的初步数据为OL-EVS/I.V的假设提供了基础。诱导耐受性APC，它减少 致病性TH细胞反应和通过免疫调节分子的表达抑制EA。目标3。学习 人类OL-EV在人髓磷脂Ag诱导的EAE和人源性小鼠中的影响。我们将优化 人类OL-EV的产生，并检验了人类OL-EVS/i.v的假设。具有足够的治疗效率 在EAE模型和人源化小鼠中，以确定在这种类似人类系统中的小鼠发现是否平行。