Oligodendrocyte extracellular vesicles: a novel therapy for CNS autoimmunity

摘要：少突胶质细胞胞外囊泡：治疗中枢神经系统自身免疫的新方法。 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， 由于全身免疫抑制，可能会有严重的副作用。多发性硬化研究的一个长期目标是 设计一种针对抗原的治疗方法，只抑制有害的免疫反应，而让其余的 免疫系统完好无损。抗原特异性治疗的前提是确定靶标抗原。女士 发病机制被广泛认为是由抗髓鞘AGS的自身免疫所驱动的。不过，相关的银(S) 多发性硬化症仍是一种推测，有可能这些AGS在不同的患者之间，随着时间的推移是相同的 有耐心的。许多针对抗原特异性抑制自身免疫性神经炎的方法已被证明 在实验性自身免疫性脑脊髓炎(EAE)中，MS的动物模型。 通过在非炎症性环境中提供相同的自体银来建立外周对自体银的耐受性(例如，在……里面 PBS)通过各种途径，例如静脉注射、口服或鼻腔注射。然而，这些实验性的翻译 MS患者中相关AGS的不确定性阻碍了MS治疗策略的实施。在……里面 针对这一问题，我们推断，如果我们使用少突胶质细胞(Ol)来源的耐受诱导 细胞外小泡(Ol-EVS)，它自然包含大部分或全部髓鞘AGs，不需要 确定每个患者的相关髓鞘银(S)。此外，我们还假设了静脉注射。注入Ol-EVS将 抑制EAE，类似于有充分证据的静脉注射。游离自体多肽诱导耐受性。事实上，我们的数据显示 Ol-Evs包含了所有相关的髓鞘AGS和On静脉注射。注射改善正在进行的银屑病患者的EAE 依赖的方式，表明Ol-EVS可以作为MS的通用治疗剂。 更多的初步数据，我们假设人和小鼠的OL-EV含有所有相关的髓鞘抗原，并且 静脉注射。给药可改善各种髓鞘AGS所致的EAE。我们还假设这一点 作用依赖于抗原，并由干扰素-/IL-27/PD-L1轴介导。这一假设将在以下方面得到检验 目的：1.确定OL-EVS对几种EAE模型的治疗效果。自.以来 本项目的意义在于研究OL-EVS作为一种潜在的治疗MS的方法，我们还不知道相关的 AG(S)在MS中，我们将检验OL-EVS/i.V.的假设。能抑制任何髓磷脂抗原诱导的EAE，因为 所有相关的AGS都存在于OL-EVS中。目的2.明确OL-EVS抑制EAE的机制。 我们的初步数据为Ol-EVS/i.v.诱导产生耐受性的APC，它会减少 致病Th细胞通过免疫调节分子的表达应答和抑制EAE。目标3.学习 人Ol-Evs对人髓鞘抗原诱导的EAE和人源化小鼠的影响。我们将优化 生产人OL-EVS，并检验人OL-EVS/IV.有足够的治疗效果 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似人类的系统相似。

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.