Erythropoietin mediated immunoregulation in murine lupus nephritis
促红细胞生成素介导的小鼠狼疮性肾炎的免疫调节
基本信息
- 批准号:10328488
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-02-15 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:Adrenal Cortex HormonesAdultAgonistAnemiaAnimal ExperimentsAnimalsAutoantibodiesAutoimmune DiseasesAutoimmune ResponsesB-LymphocytesCell physiologyCellsChronicClinicalComplexDataDefectDevelopmentDiseaseDoseElementsErythrocytesErythropoiesisErythropoietinErythropoietin ReceptorFlareFrequenciesGleanGrantHelper-Inducer T-LymphocyteHormonesHumanIL2RA geneImmuneImmunityImmunologicsImmunosuppressionImmunosuppressive AgentsInbreedingInflammationInjury to KidneyInterleukin-2KidneyKidney DiseasesKnockout MiceLiftingLinkLiteratureLupusLupus ErythematosusLupus NephritisMediatingMediator of activation proteinMedicalMolecularMorbidity - disease rateMouse StrainsMusNucleoproteinsOrganOutcomePathogenesisPathogenicityPathologicPatientsPlayProcessProductionPublishingReceptor ActivationReceptor SignalingRecombinant ErythropoietinRegulatory T-LymphocyteRenal functionRoleSelf ToleranceSeveritiesSeverity of illnessStructure of germinal center of lymph nodeSystemic Lupus ErythematosusT-LymphocyteTestingTherapeuticTherapeutic AgentsTissuesTranslatingWorkautoreactive B cellautoreactive T cellautoreactivitycomparativeexperimental studyhuman subjectimmunoregulationimprovedimproved outcomein vivoknock-downmouse modelpathogenic autoantibodiespre-clinicalpreventreceptorrestrainttranslational study
项目摘要
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.
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理的不同要素。
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Th 17、T滤泡辅助细胞
(TFH)和Th 1,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CD 4 + CD 25 + CD 127 lo 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
Th 17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Th 17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
Th 17、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。
项目成果
期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Erythropoietin in Lupus: Unanticipated Immune Modulating Effects of a Kidney Hormone.
- DOI:10.3389/fimmu.2021.639370
- 发表时间:2021
- 期刊:
- 影响因子:7.3
- 作者:Eswarappa M;Cantarelli C;Cravedi P
- 通讯作者:Cravedi P
Differences in Humoral and Cellular Vaccine Responses to SARS-CoV-2 in Kidney and Liver Transplant Recipients.
- DOI:10.3389/fimmu.2022.853682
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
Endogenous erythropoietin has immunoregulatory functions that limit the expression of autoimmune kidney disease in mice.
- DOI:10.3389/fimmu.2023.1195662
- 发表时间:2023
- 期刊:
- 影响因子:7.3
- 作者:
- 通讯作者:
Kidney immunology: embracing the complexity to advance the field.
- DOI:10.1093/ckj/sfab222
- 发表时间:2022-03
- 期刊:
- 影响因子:4.6
- 作者:Riella LV;Cravedi P
- 通讯作者:Cravedi P
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Paolo Cravedi其他文献
Paolo Cravedi的其他文献
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{{ truncateString('Paolo Cravedi', 18)}}的其他基金
High-throughput identification and transcriptional analysis of autoreactive T cells in individuals with membranous nephropathy.
膜性肾病患者自身反应性 T 细胞的高通量鉴定和转录分析。
- 批准号:
10725558 - 财政年份:2023
- 资助金额:
$ 42.38万 - 项目类别:
Deciphering the Molecular Mechanisms of Response to COVID Vaccine in Kidney Transplant Recipients
解读肾移植受者对新冠疫苗反应的分子机制
- 批准号:
10668154 - 财政年份:2023
- 资助金额:
$ 42.38万 - 项目类别:
Mechanisms of complement-mediated podocyte injury in FSGS
FSGS 中补体介导的足细胞损伤机制
- 批准号:
10115529 - 财政年份:2019
- 资助金额:
$ 42.38万 - 项目类别:
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