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

基本信息

批准号：
10361415
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10361415
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 multiple sclerosis treatment neuroinflammation novel therapeutics particle peripheral tolerance programmed cell death ligand 1 prophylactic reconstitution response side effect success vesicular release

项目摘要

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：少突胶质细胞外囊泡：中枢神经系统自身免疫的一种新疗法。目前多发性硬化症 (MS) 的治疗以抗原 (Ag) 非特异性方式针对免疫系统，由于全身性免疫抑制而具有潜在的严重副作用，这是多发性硬化症研究的一个长期目标。设计一种 Ag 特异性疗法，仅抑制有害的免疫反应，同时保留其余的免疫反应 Ag特异性治疗的先决条件是识别目标Ag。人们普遍认为发病机制是由针对髓磷脂抗原的自身免疫驱动的，然而，相关的抗原。在多发性硬化症中的作用仍然是推测性的，这些抗原可能在患者之间存在差异，并且随着时间的推移，同一许多Ag特异性抑制自身免疫性神经炎症的方法已被证实。在实验性自身免疫性脑脊髓炎（EAE）中，这些方法依赖于多发性硬化症的动物模型。通过在非炎症环境中（例如，在 PBS）通过各种途径，例如静脉内（i.v.）、口服或鼻腔然而，这些实验的翻译。由于多发性硬化症患者中相关抗原的不确定性，多发性硬化症治疗策略受到了阻碍。为了解决这个问题，我们推断，如果我们使用少突胶质细胞 (Ol) 衍生的耐受诱导细胞外囊泡 (Ol-EV) 天然含有大部分或全部髓磷脂 Ag，因此没有必要此外，我们还确定静脉注射 Ol-EV 将有助于识别每个患者的相关髓磷脂 Ag。抑制 EAE，类似于有据可查的游离自肽静脉注射耐受诱导。 Ol-EVs 含有所有相关的髓磷脂 Ag，并且静脉注射后可改善 Ag-中持续的 EAE。基于这些，表明 Ol-EVs 可以成为 MS 的通用治疗剂。额外的初步数据，我们追求人类和小鼠 Ol-EV 包含所有相关的髓磷脂 Ag，并且静脉注射后会改善由各种髓磷脂抗原引起的 EAE。该效应是Ag依赖性的并且由IFN-γ/IL-27/PD-L1轴介导，该假设将在下面进行检验。具体目标：目标 1. 确定 Ol-EV 在多种 EAE 模型中的治疗效果。该项目的意义在于研究 Ol-EVs 作为 MS 的潜在疗法，但我们不知道相关的 Ag(s) 在 MS 中，我们将检验 OL-EVs/i.v. 可以抑制任何髓磷脂 Ag 诱导的 EAE 的假设，因为所有相关 Ag 均存在于 OL-EV 中。目标 2. 定义 Ol-EV 抑制 EAE 的机制。我们的初步数据为 Ol-EVs/i.v. 诱导耐受性 APCs 的假设提供了基础。目的 3. 研究。我们将优化人类 Ol-EV 对人类髓磷脂 Ag 诱导的 EAE 以及人源化小鼠的影响。生产人类 Ol-EV，并检验人类 Ol-EV/i.v. 具有足够治疗功效的假设在 EAE 模型和人源化小鼠中，以确定小鼠的发现是否与这个类人系统相似。