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：少突胶质细胞胞外囊泡：一种治疗中枢神经系统自身免疫的新方法。