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

摘要 自身免疫性葡萄膜炎(AU)是全球范围内导致视力残疾的主要原因。当前的临床治疗 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，需要对AU进行合理、安全、有效的治疗。视网膜的细胞毒性破坏和 辅助性T细胞1(Th1)和Th17细胞相关组织是AU的主要病理特征，因此设计 有效的病因治疗应以沉默Th1/Th17细胞为目标。一种治疗策略 抑制自身反应性T细胞是利用间充质干细胞(MSCs)作为其免疫抑制因子 这种能力在文化、动物模型和患者中得到了广泛的展示。然而，大量的变化在 由于供体、培养条件和组织来源的不同，骨髓间充质干细胞的发育受到阻碍。 MSC疗法。最近，间充质干细胞来源的胞外囊泡(MSC-EVS)已成为一种新兴的 MSC治疗，因为它们在很大程度上概括了以前归因于MSCs的广泛治疗效果。 此外，电动汽车显示出固有的细胞靶向性，循环中的稳定性而不会失去功能，以及优越的 无细胞治疗的安全性，表明MSC-EVS比细胞治疗有多种优势。 重要的是，我们最近表明，给予MSC-EVS可以预防自体免疫性疾病的发生。 小鼠模型、1型糖尿病、实验性非盟(EAU)和干燥综合征。因此，这一目标是 建议开发一种安全有效的治疗AU的MSC-EV疗法。总体目标是定义 MSC-EV抑制自身免疫和制定策略最大化其自身免疫的潜在机制 治疗效果。为了实现我们的目标，目标1将确定电动汽车的治疗因素 负责MSC-EV在AU中的中介作用，定义MSC-EV的潜在机制 抑制Th1/Th17细胞。目标2将开发策略，以最大限度地发挥MSC- 电动汽车。AIM 3将制定策略，加强MSC-EV向目标细胞的传递。这项提议的成功 研究将为电动汽车的合理设计提供必要的见解和有价值的信息 干预措施，最终导致了新型、安全和临床可行的MSC治疗方法的开发。 用于非盟治疗的EVS。 好了！

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. !