Erythropoietin mediated immunoregulation in murine lupus nephritis

摘要 系统性 特征化的 生产 治疗 其中 红斑狼疮 (SLE) 是一种慢性、可能致命的自身免疫性疾病 自身反应性 T 细胞和 B 细胞的异常激活导致 导致广泛组织和器官损伤的自身抗体。当前 策略严重依赖皮质类固醇和免疫抑制剂， 受到次优疗效和严重发病率负担的限制。 , 上 确定替代的、更安全和更全面的目标方法 需要探索疾病发病机制的不同要素。 我们新发布的初步数据支持了这一具有争议性且有趣的概念 促红细胞生成素（EPO）是一种主要由成人肾脏产生的激素， 在控制狼疮自身免疫反应和改善自身免疫反应方面发挥着意想不到的作用 临床结果。超越 EPO 在红细胞中的既定作用 开发中，我们的新数据表明 EPO a) 改善了疾病的严重程度 狼疮小鼠模型，b) 抑制小鼠和人类 Th17、滤泡辅助 T 细胞 (TFH) 和 Th1，同时增加滤泡调节性 T 细胞 (Tfr)，c) 诱导和 稳定 Treg，d) 抑制生发中心 B 细胞形成和自身抗体 生产。我们已经确定了将 EPO 与其中一些联系起来的分子机制 效果并表明它们适用于给予临床使用剂量的 EPO 的人类。欧洲专利局 用于纠正贫血的治疗剂量可增加循环频率 人类受试者中的 CD4 CD25 CD127lo Treg。总而言之，我们的研究结果支持 本项目要测试以下假设：EPO 直接抑制自身反应 Th17 和 TFH，同时诱导和维持 Treg 和 Tfr 降低狼疮疾病的严重程度。 我们将通过确定外源性和肾源性的影响来检验这一假设。 EPO 对小鼠狼疮的作用（目标 1），破译 EPO 的作用机制 选择性抑制 Th17 和 TFH（目标 2），而 EPO 促进 Treg/Tfr 诱导并 稳定性（目标 3）。拟议的工作将定义欧洲专利局作为自我调解者的作用 耐受性并将描述 EPO 作用背后的细胞和分子机制 Th17、TFH 和 Treg/Tfr。除了破译机制之外，这些研究还将 提供有关 EPO 作为治疗剂改善病情的临床前数据 动物中的疾病活动，这些发现可能会转化为系统性红斑狼疮患者。

Abstract Systemic characterized production treatment which lupus erythematosus (SLE) is a chronic, potentially fatal autoimmune disease by abnormal activation of autoreactive T and B cells resulting in the of autoantibodies that cause widespread tissue and organ damage. Current strategies rely heavily corticosteroids and immunosuppressive agents, are limited by suboptimal efficacy and by a significant burden of morbidity. , on Identification of alternative, safer and more comprehensive approaches targeting different elements of disease pathogenesis need to be explored. Our new published and preliminary data support the provocative and intriguing concept that erythropoietin (EPO), a hormone produced predominantly by the kidney in adults, plays an unanticipated role in controlling autoimmune response in lupus and improving clinical outcomes. Expanding beyond EPO's established role in erythrocyte development, our new data demonstrate that EPO a) improves disease severity in murine models of lupus, b) inhibits mouse and human Th17, T follicular helper cells (TFH), and Th1, while it increases T follicular regulatory cells (Tfr), c) induces and stabilizes Treg, and d) inhibits germinal center B cell formation and autoantibody production. We have identified molecular mechanisms that link EPO to some of these effects and show that they apply to humans given clinically used doses of EPO. EPO therapy, at doses used to correct anemia, augments frequencies of circulating CD4+CD25+CD127lo Treg in human subjects. Altogether, our findings support the following hypothesis to be tested in this project: EPO directly inhibits autoreactive Th17 and TFH, and simultaneously induces and maintains Treg and Tfr, together reducing disease severity in lupus. We will test this hypothesis by determining the effects of exogenous and kidney-derived EPO on murine lupus (aim 1), deciphering the mechanisms through which EPO selectively inhibits Th17 and TFH (aim 2), while EPO promotes Treg/Tfr induction and stability (aim 3). The proposed work will define the role of EPO as a mediator of self- tolerance and will delineate cellular and molecular mechanisms underlying EPO's effects on Th17, TFH, and Treg/Tfr. In addition to deciphering mechanisms, the studies will provide preclinical data on the utility of EPO as a therapeutic agent for improving disease activity in animals, findings that could potentially be translated to SLE patients.