Extracellular Vesicles Produced by Mesenchymal Stem Cells as Novel Therapy for Autoimmune Uveitis

间充质干细胞产生的细胞外囊泡作为自身免疫性葡萄膜炎的新疗法

• 批准号: 10357942
• 负责人: Ryang Hwa Lee
• 金额: $ 36.01万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357942
• 关键词: Address; Animal Model; Antigen-Presenting Cells; Apolipoprotein A-I; Arrestins; Autoimmune Diseases; Autoimmunity; Binding; Binding Proteins; Biodistribution; Blood Circulation; CD81 gene; CISH gene; Cells; Clinical; Clinical Treatment; Development; Engineering; Goals; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; In Vitro; Infusion procedures; Insulin-Dependent Diabetes Mellitus; Integrin Binding; Intervention; Ligands; Link; Lymphoid; Mediating; Mesenchymal Stem Cells; Molecular; Molecular Profiling; Mus; Neuraminidase; Pathologic; Pathway interactions; Patients; Peptides; Prevention; Property; Proteins; Proteomics; Recombinants; Research; Research Proposals; Retina; Safety; Sialic Acids; Sjogren' s Syndrome; Source; Splenocyte; Surface; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Variant; Visual; autoimmune uveitis; autoreactive T cell; autoreactivity; base; cell type; cytokine; cytotoxic; design; disability; effective therapy; extracellular vesicles; immunoregulation; in vivo; insight; loss of function; lumican; lymphoid organ; mouse model; novel; novel strategies; novel therapeutics; overexpression; prevent; rational design; receptor; sialoadhesin; side effect; stem cell therapy; success; uptake

Abstract Autoimmune uveitis (AU) is a major cause of visual disability worldwide. Clinical treatment currently involves the use of immunosuppressive drugs, but serious side effects limit their long-term application. In this sense, safer and more effective therapies for AU are needed. The cytotoxic destruction of the retina and related tissues by T helper 1 (Th1) and Th17 cells is the key pathological feature of AU, hence the design of efficient cause-addressing AU treatments should target silencing of Th1/Th17 cells. One therapeutic strategy to suppress the auto-reactive T cells is the use of mesenchymal stem cells (MSCs) as their immune suppressive abilities have been extensively shown in cultures, animal models and patients. However, large variations in MSCs, due to the differences in donors, culture conditions, and tissue sources impede developing of robust MSC therapy. Lately, MSC-derived extracellular vesicles (MSC-EVs) have become an emerging alternative to MSC therapy, as they recapitulate to a large extent the broad therapeutic effects previously attributed to MSCs. Also, EVs display intrinsic cell targeting-properties, stability in circulation without loss of function, and superior safety profile of a cell-free treatment, suggesting MSC-EVs have multiple advantages over cell treatment. Importantly, we recently showed that administration of MSC-EVs prevent the onset of autoimmune disease in murine models, type 1 diabetes, experimental AU (EAU), and Sjogren's syndrome. Therefore, the goal of this proposal is to develop a safe and effective MSC-EV therapy for AU. The overall objective is to define the underlying mechanism by which MSC-EVs suppress autoimmunity and develop strategies to maximize their therapeutic efficacy. To achieve our objective, Aim 1 will identify the therapeutic factors in EVs that are responsible for the MSC-EV mediated action in Au, defining the underlying mechanism by which MSC-EVs suppress Th1/Th17 cells. Aim 2 will develop strategies to maximize the immune suppressive effect of MSC- EVs. Aim 3 will develop strategies to enhance MSC-EV delivery to the target cells. The success of the proposal research will provide essential insights and valuable information for the rational design of EV-based interventions, ultimately leading to a development of the novel, safe and clinically feasible therapy with MSC- EVs for AU treatment. !

摘要 自身免疫性葡萄膜炎（Au）是世界范围内视力残疾的主要原因。目前临床治疗 涉及免疫抑制药物的使用，但严重的副作用限制了它们的长期应用。在这 因此，需要更合理、更安全、更有效的治疗方法来治疗Au。视网膜的细胞毒性破坏， 辅助性T细胞1（Th 1）和Th 17细胞对相关组织的作用是Au的关键病理特征，因此设计了 有效的病因解决Au治疗应该靶向Th 1/Th 17细胞的沉默。一种治疗策略， 抑制自身反应性T细胞是使用间充质干细胞（MSC）作为其免疫抑制剂 能力已经在培养物、动物模型和患者中广泛显示。然而， 骨髓间充质干细胞由于供体、培养条件和组织来源的差异，阻碍了其稳健的生长。 MSC疗法。最近，MSC衍生的细胞外囊泡（MSC-EV）已经成为替代MSC的新兴选择。 MSC疗法，因为它们在很大程度上概括了先前归因于MSC的广泛治疗效果。 此外，EV显示出固有的细胞靶向性质、在循环中的稳定性而不丧失功能，以及优异的上级生物相容性。 无细胞治疗的安全性特征，表明MSC-EV相对于细胞治疗具有多种优势。 重要的是，我们最近表明，MSC-EV的管理，防止自身免疫性疾病的发生， 鼠模型、1型糖尿病、实验性Au（EAu）和舍格伦综合征。因此，这一目标 目的是为Au患者开发一种安全有效的MSC-EV疗法。总体目标是确定 MSC-EV抑制自身免疫并制定策略以最大限度地提高自身免疫的潜在机制 疗效为了实现我们的目标，目标1将确定EV的治疗因素， 负责MSC-EV介导的Au作用，定义了MSC-EV 抑制Th 1/Th 17细胞。目的2将开发策略，以最大限度地发挥MSC的免疫抑制作用。 电动车目标3将开发策略以增强MSC-EV向靶细胞的递送。提案的成功 研究将为电动汽车的合理设计提供重要的见解和有价值的信息。 干预，最终导致开发新的，安全的和临床可行的治疗与MSC- 用于Au治疗的EV。 !