Erythropoietin mediated immunoregulation in murine lupus nephritis

摘要 系统性 特征化 生产 治疗 哪一个 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细胞的异常激活导致 会导致广泛的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的发病率负担的限制。 ， 在……上面 确定针对目标的替代、更安全和更全面的方法 疾病的发病机制需要探索不同的因素。 我们最新公布的和初步的数据支持这一具有挑衅性和耐人寻味的概念 促红细胞生成素(EPO)，一种主要由成人肾脏产生的激素， 在控制狼疮自身免疫反应和改善病情方面发挥了意想不到的作用 临床结果。超越促红细胞生成素在红细胞中的既定作用 发展，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，以及d)抑制生发中心B细胞的形成和自身抗体 制作。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。促红细胞生成素 治疗剂量用于纠正贫血，增加循环频率 人外周血中CD_4~+CD25~+CD127~+T细胞亚群的变化总而言之，我们的发现支持 以下假设将在本项目中进行验证：促红细胞生成素直接抑制自身反应 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(目标1)，破译EPO通过 选择性地抑制Th17和TFH(目标2)，而EPO促进Treg/TFR的诱导和 稳定性(目标3)。拟议的工作将定义促红细胞生成素作为自我调节的角色 耐受性，并将阐明EPO作用的细胞和分子机制 Th17、TFH和Treg/Tfr。除了破译机制外，这些研究还将 提供促红细胞生成素作为治疗剂的临床前数据，以改善 在动物中的疾病活动性，这一发现可能转化为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.