Complement regulates macrophage and platelet function in kidney transplants
补体调节肾移植中的巨噬细胞和血小板功能
基本信息
- 批准号:10681424
- 负责人:
- 金额:$ 62.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-17 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAntibodiesAntibody TherapyApoptoticAutoantibodiesAutoantigensAutoimmunityBindingBiopsyBlood PlateletsC1q deficiencyCellsChemotactic FactorsChronicClinical TrialsComplementComplement 1qComplement 3aComplement 5aComplement ActivationComplement InactivatorsComplement component C1rComplement component C1sComplement component C5EndotheliumGenerationsGoalsHumanImmune responseInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjuryIschemiaIsoantibodiesKidney TransplantationLabelMacrophageMediatingMediatorMusMyeloid CellsNK Cell ActivationNatural Killer CellsOrganOrgan TransplantationPathway interactionsPatientsPattern recognition receptorProductionPublicationsRecoveryReperfusion TherapySeriesSerine Proteinase InhibitorsTechnologyTestingTherapeuticTransplantationVascular EndotheliumVesicleWorkantibody-mediated rejectioncomplement 1q receptordelayed graft functiondigitalextracellular vesiclesimmunogenicinhibitorinhibitor therapyneutrophilorgan injuryplatelet functionpreservationreceptor bindingreceptor functionrecruitresponsesuccessvesicular release
项目摘要
ABSTRACT
The potential for complement activation during organ recovery, ischemia reperfusion and antibody-mediated
rejection (AMR) is well-recognized. As a result, numerous therapeutic inhibitors of complement have been
developed and tested in the treatment of AMR. Inhibitors of the terminal complement component C5, and more
recently, C1 the first component of the classical pathway have been tested most extensively. Extensive evidence
indicates C1q functions as a pattern recognition receptor (PRR) that binds apoptotic cells and mediates a non-
inflammatory clearance by macrophages. In fact, C1q deficient patients and mice do not clear apoptotic cells
efficiently and develop florid autoimmunity. Remarkably little is known about the effects of C1q in transplantation.
However, in recent clinical trials, injury caused by delayed graft function has been diminished by treatment with
C1 inhibitor (C1inh), a serine protease inhibitor that terminates complement activation, but leaves C1q intact.
These results invite the obvious question: Does C1inh work because it truncates the complement cascade and
decreases production of downstream inflammatory mediators or does C1inh work because it leaves C1q intact
to modulate macrophages and cells that express C1q receptors? Of course, these are not mutually exclusive.
More is known about the functions of C5a in antibody induced inflammation. C5a is a potent chemoattractant
and activator of neutrophils and macrophages. However, platelets also express C5aR. We have demonstrated
that platelets accumulate within minutes after antibody binds and activates complement on graft endothelium.
We propose the hypothesis that C1q down modulates whereas C5a upregulates inflammatory responses in
transplants; therefore preserving C1q functions and inhibiting C5a functions will decrease AMR. We will test this
hypothesis in the following 3 specific aims: 1) Test the capacity of C1q to function as a PRR to remove potentially
immunogenic extracellular vesicles during reperfusion after transplantation and decrease the induction of allo-
and autoantibody responses. 2) Test the effects of C5a on neutrophil and macrophage functions in ischemia-
reperfusion and chronic AMR. 3) Test the effects of C5a on platelet functions in acute and chronic AMR. These
specific aims encompass and enhance common threads of our PPG that focuses on mechanisms underlying
AMR. The goal of this proposal is to provide the basis for rational therapeutic enhancement of the beneficial
functions of C1q in transplants and modulation of proinflammatory effects of C3a and C5a.
抽象的
器官恢复期间的补体激活的潜力,缺血再灌注和抗体介导
拒绝(AMR)已得到充分认可。结果,补体的许多治疗抑制剂已经
在AMR治疗中开发和测试。末端补体组件C5的抑制剂,更多
最近,C1经典途径的第一个组成部分已经进行了最广泛的测试。广泛的证据
表明C1Q充当模式识别受体(PRR),该受体结合凋亡细胞并介导非 -
巨噬细胞的炎症清除。实际上,C1Q缺乏患者和小鼠没有清除凋亡细胞
有效并发展蓬松的自身免疫性。关于C1Q在移植中的影响知之甚少。
然而,在最近的临床试验中,通过治疗的治疗减少了由延迟移植功能造成的伤害
C1抑制剂(C1INH),一种丝氨酸蛋白酶抑制剂,可终止补体激活,但使C1Q完好无损。
这些结果引起了一个明显的问题:C1inh是否有效,因为它截断了补充级联和
减少下游炎症介质的产生或C1inh起作用,因为它使C1Q完好无损
调节表达C1Q受体的巨噬细胞和细胞?当然,这些不是相互排斥的。
有关C5A在抗体诱导的炎症中的功能的知识。 C5A是一种有效的趋化因子
和中性粒细胞和巨噬细胞的激活剂。但是,血小板也表达C5AR。我们已经证明了
该血小板在抗体结合并激活移植物内皮上的数分钟内积聚。
我们提出了以下假设:C1Q下降调节,而C5A上调了炎症反应
移植;因此,保留C1Q功能并抑制C5a功能将降低AMR。我们将测试这个
在以下3个特定目的中的假设:1)测试C1Q作为PRR的能力,以消除潜在的去除
移植后再灌注过程中的免疫原性细胞外囊泡,并减少同种的诱导
和自身抗体反应。 2)测试C5a对缺血性中性粒细胞和巨噬细胞功能的影响
再灌注和慢性AMR。 3)测试C5A对急性和慢性AMR血小板功能的影响。这些
具体目的包括并增强我们PPG的共同线程,该线程侧重于基础机制
AMR。该提案的目的是为有益的理性治疗增强提供基础
C1Q在移植中的功能以及C3A和C5A的促炎作用的调节。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Balancing the View of C1q in Transplantation: Consideration of the Beneficial and Detrimental Aspects.
- DOI:10.3389/fimmu.2022.873479
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:Khedraki R;Noguchi H;Baldwin WM 3rd
- 通讯作者:Baldwin WM 3rd
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William M Baldwin其他文献
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{{ truncateString('William M Baldwin', 18)}}的其他基金
Complement regulates macrophage and platelet function in kidney transplants
补体调节肾移植中的巨噬细胞和血小板功能
- 批准号:
10490858 - 财政年份:2021
- 资助金额:
$ 62.56万 - 项目类别:
Complement regulates macrophage and platelet function in kidney transplants
补体调节肾移植中的巨噬细胞和血小板功能
- 批准号:
10337999 - 财政年份:2021
- 资助金额:
$ 62.56万 - 项目类别:
Platelets and complement in antibody-mediated rejection
抗体介导的排斥反应中的血小板和补体
- 批准号:
9086203 - 财政年份:2016
- 资助金额:
$ 62.56万 - 项目类别:
Platelets and complement in antibody-mediated rejection
抗体介导的排斥反应中的血小板和补体
- 批准号:
9283289 - 财政年份:2010
- 资助金额:
$ 62.56万 - 项目类别:
Complement and Platelets in Antibody-Medicated Rejection
抗体排斥反应中的补体和血小板
- 批准号:
7891951 - 财政年份:2010
- 资助金额:
$ 62.56万 - 项目类别:
Complement and Antibody in the Pathogenesis of AGA
AGA发病机制中的补体和抗体
- 批准号:
6739494 - 财政年份:2003
- 资助金额:
$ 62.56万 - 项目类别:
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