Erythropoietin mediated immunoregulation in murine lupus nephritis

摘要 系统性 特征 生产 治疗 这 红斑狼疮（SLE）是一种慢性、潜在致命的自身免疫性疾病 通过自身反应性T和B细胞的异常激活， 自身抗体会导致广泛的组织和器官损伤。电流 策略严重依赖皮质类固醇和免疫抑制剂， 受限于次优疗效和显著的发病率负担。 , 对 确定替代的、更安全和更全面的办法， 需要探索疾病发病机制的不同要素。 我们新发表的初步数据支持这一挑衅性和有趣的概念 促红细胞生成素（EPO），一种主要由成人肾脏产生的激素， 在控制狼疮的自身免疫反应和改善 临床结果。超越EPO在红细胞中的既定作用 开发，我们的新数据表明，EPO a）改善疾病的严重程度， 狼疮的鼠模型，B）抑制小鼠和人Th17、T滤泡辅助细胞 (TFH)和Th1，同时增加T滤泡调节细胞（Tfr），c）诱导和 稳定Treg，和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， 并显示它们适用于给予临床使用剂量的EPO的人。EPO 在用于纠正贫血的剂量下，治疗增加了循环的频率， 人受试者中的CD4 + CD25 + CD127lo Treg。总之，我们的研究结果支持了 在本项目中将检验以下假设：EPO直接抑制自身反应性 Th17和TFH，并同时诱导和维持Treg和Tfr， 降低狼疮的疾病严重程度。 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（目的1），解读EPO 选择性抑制Th17和TFH（目的2），而EPO促进Treg/Tfr诱导， 稳定性（目标3）。拟议的工作将确定EPO作为自我调节者的作用， 并将阐明EPO作用的细胞和分子机制 Th17、TFH和Treg/Tfr。除了破译机制，这些研究将 提供了关于EPO作为治疗剂用于改善 疾病活动的动物，发现可能会转化为SLE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.