CpG and B cells, pretreated ex-vivo with natural IgM, protect against renal IRI
用天然 IgM 进行离体预处理的 CpG 和 B 细胞,可预防肾 IRI
基本信息
- 批准号:9916737
- 负责人:
- 金额:$ 36.34万
- 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:2018-05-02 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Renal Failure with Renal Papillary NecrosisAdoptive TransferAdverse drug effectAnimal ModelAnti-Inflammatory AgentsAntigensAntiinflammatory EffectAutoantibodiesAutoimmune ProcessB cell therapyB-LymphocytesBindingBloodBrainCardiac MyocytesCardiac Surgery proceduresCell TherapyCell physiologyCellsCessation of lifeChronic Kidney FailureClinicalClinical DataDataDevelopmentDiseaseEconomicsEffector CellEnd stage renal failureEndotoxinsEventFDA approvedHeartHourHumanImmuneImmunoglobulin MInbred NOD MiceInflammationInflammatoryInflammatory ResponseInfusion proceduresInjuryInjury to KidneyIntravenousIntravenous infusion proceduresInvestigationInvestigational DrugsIschemiaKidneyKnockout MiceLipidsMediatingModelingMorbidity - disease rateMusNatural IncreasesNeuronsOrgan DonorPharmaceutical PreparationsPharmacotherapyPhenotypePhysiologicalPlasmaProductionPublic HealthPublicationsReceptors, Antigen, B-CellRegulatory T-LymphocyteRoleSepsisStudy modelsT cell differentiationT-LymphocyteTNF geneTestingTranslationsTubular formationVaccinesallograft rejectionanti-IgMcell injurycostdosageeffective therapyhigh riskin vivoinnovationinsulitismacrophagemortalitymouse modelpreventprotective effectrenal ischemiaside effecttargeted treatment
项目摘要
Summary/Abstract
Acute kidney injury (AKI) is a common problem and associated with increased morbidity and mortality and
development of chronic kidney disease (CKD) and in some cases end stage renal disease (ESRD). There are no
FDA approved drugs to prevent AKI, and this is in part related to systemic side effects of these drugs. In this
application we propose two approaches to prevent AKI. Firstly, we propose the pre-emptive use of ex-vivo
induced regulatory B cell infusion to prevent AKI. We have shown that isolated B cells, pretreated ex-vivo with
IgM or CpG, develop into regulatory B cells (Bregs), which when intravenously infused into mice, 24 hours
before renal ischemia, protect mice from renal ischemia induced AKI and we show that protection is mediated
by inhibiting the ischemia induced inflammatory response (IIR) which is primarily responsible for AKI. We
show that the infused Bregs interact and regulate in-vivo NKT-1 cell, which normally amplify the IIR. We
would like to also examine how IgM or CpG pretreatments switch B cells into Bregs. Secondly, we propose that
CpG ,when pre-emptively administered to mice, prevents AKI. Others have shown that CpG when
administered 3 or 4 days or 1 hour before the ischemic event in murine hearts or brain, protects these mice from
ischemia induced damage. CpG,when administered 1 hour before the ischemic event, protects by enhancing
tolerance of non-immune cells (i.e cardiomyocytes, neurons) to ischemia induced cell injury/death. However,
we do not understand how CpG protects against ischemic damage when given 3 or 4 days before ischemia and
there are no studies on the protective effect of CpG in AKI. We propose that CpG when given at -3 or -4 days
induces production of high in-vivo natural IgM, which we have shown is broadly anti-inflammatory and protects
kidneys by inhibiting IIR. We would like, in this application, to investigate the mechanism for CpG induced
protection and evaluate if CpG and Bregs, when combined is more protective. We will use two murine models
of AKI i.e ischemia and LPS induced sepsis to determine if Bregs and/or CpG inhibit innate inflammation. This
project has a good chance for translation into humans as CpG is currently used in vaccines and we induced ex-
vivo human Bregs with IgM and CpG pretreatment. Both Bregs and/or CpG can be used to prevent AKI in high
risk cardiac surgery and in deceased organ donors or recipients.
摘要/摘要
急性肾损伤(阿基)是一种常见的问题,与发病率和死亡率增加相关,
慢性肾病(CKD)和某些情况下终末期肾病(ESRD)的发展。没有
FDA批准了预防阿基的药物,这部分与这些药物的全身副作用有关。在这
应用中,我们提出了两种预防阿基的方法。首先,我们提出了先发制人的使用离体
诱导调节性B细胞输注以预防阿基。我们已经表明,分离的B细胞,预处理离体与
IgM或CpG,发展成调节性B细胞(BCRs),当静脉内输注到小鼠中时,24小时
在肾缺血前,保护小鼠免受肾缺血诱导的阿基,我们表明保护作用是介导的,
通过抑制主要导致阿基的缺血诱导的炎症反应(IIR)。我们
显示输注的BKT相互作用并调节体内NKT-1细胞,其通常放大IIR。我们
我也想研究IgM或CpG预处理如何将B细胞转化为BCLs。第二,我们建议,
CpG在预先给予小鼠时可预防阿基。其他研究表明,当CpG
在鼠心脏或脑中缺血事件之前3或4天或1小时施用,保护这些小鼠免于
缺血引起的损伤。CpG在缺血事件前1小时给药时,通过增强缺血性事件的发生率来保护缺血性事件。
非免疫细胞(即心肌细胞、神经元)对缺血诱导的细胞损伤/死亡的耐受性。然而,在这方面,
我们不了解在缺血前3或4天给予CpG如何保护缺血性损伤,
没有关于CpG在阿基中的保护作用的研究。我们建议在-3天或-4天给予CpG
诱导产生高的体内天然IgM,我们已经表明,这是广泛的抗炎和保护
肾脏通过抑制IIR。在本申请中,我们希望研究CpG诱导的细胞凋亡的机制。
保护,并评估CpG和BcG组合时是否更具保护性。我们将使用两种小鼠模型
阿基即缺血和LPS诱导的脓毒症,以确定BcG和/或CpG是否抑制先天性炎症。这
项目有很好的机会翻译成人类,因为CpG目前用于疫苗,我们诱导了前-
用IgM和CpG预处理的体内人BCLs。BCG和/或CpG均可用于预防高血压患者的阿基。
心脏手术风险和死亡的器官捐赠者或接受者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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PETER LOBO其他文献
PETER LOBO的其他文献
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{{ truncateString('PETER LOBO', 18)}}的其他基金
Naturally Occurring IgM Anti-Leucocyte Autoantibodies Protect Against Renal IRI
天然存在的 IgM 抗白细胞自身抗体可预防肾 IRI
- 批准号:
7784317 - 财政年份:2010
- 资助金额:
$ 36.34万 - 项目类别:
Naturally Occurring IgM Anti-Leucocyte Autoantibodies Protect Against Renal IRI
天然存在的 IgM 抗白细胞自身抗体可预防肾 IRI
- 批准号:
8045476 - 财政年份:2010
- 资助金额:
$ 36.34万 - 项目类别:
Naturally Occurring IgM Anti-Leucocyte Autoantibodies Protect Against Renal IRI
天然存在的 IgM 抗白细胞自身抗体可预防肾 IRI
- 批准号:
8432504 - 财政年份:2010
- 资助金额:
$ 36.34万 - 项目类别:
Naturally Occurring IgM Anti-Leucocyte Autoantibodies Protect Against Renal IRI
天然存在的 IgM 抗白细胞自身抗体可预防肾 IRI
- 批准号:
8609025 - 财政年份:2010
- 资助金额:
$ 36.34万 - 项目类别:
Naturally Occurring IgM Anti-Leucocyte Autoantibodies Protect Against Renal IRI
天然存在的 IgM 抗白细胞自身抗体可预防肾 IRI
- 批准号:
8230696 - 财政年份:2010
- 资助金额:
$ 36.34万 - 项目类别:
IgM Antileucocyte Autoantibodies Inhibit Kidney Allograft Rejections
IgM 抗白细胞自身抗体抑制肾同种异体移植排斥
- 批准号:
7470315 - 财政年份:2009
- 资助金额:
$ 36.34万 - 项目类别:
Natural IgM antilymphocyte autoantibodies inhibit HIV-1
天然 IgM 抗淋巴细胞自身抗体抑制 HIV-1
- 批准号:
6553310 - 财政年份:2002
- 资助金额:
$ 36.34万 - 项目类别:
Natural IgM antilymphocyte autoantibodies inhibit HIV-1
天然 IgM 抗淋巴细胞自身抗体抑制 HIV-1
- 批准号:
6655714 - 财政年份:2002
- 资助金额:
$ 36.34万 - 项目类别:
MHC GENE PRODUCTS IN PROTECTING CELLS AGAINST NK LYSIS
MHC 基因产品保护细胞免受 NK 裂解
- 批准号:
3194754 - 财政年份:1990
- 资助金额:
$ 36.34万 - 项目类别:
MHC GENE PRODUCTS IN PROTECTING CELLS AGAINST NK LYSIS
MHC 基因产品保护细胞免受 NK 裂解
- 批准号:
3194755 - 财政年份:1990
- 资助金额:
$ 36.34万 - 项目类别:
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