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：
William M Baldwin
金额：
$ 62.56万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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：
https://reporter.nih.gov/project-details/10681424
关键词：
Acute Antibodies Antibody Therapy Apoptotic Autoantibodies Autoantigens Autoimmunity Binding Biopsy Blood Platelets C1q deficiency Cells Chemotactic Factors Chronic Clinical Trials Complement Complement 1q Complement 3a Complement 5a Complement Activation Complement Inactivators Complement component C1r Complement component C1s Complement component C5 Endothelium Generations Goals Human Immune response Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Ischemia Isoantibodies Kidney Transplantation Label Macrophage Mediating Mediator Mus Myeloid Cells NK Cell Activation Natural Killer Cells Organ Organ Transplantation Pathway interactions Patients Pattern recognition receptor Production Publications Recovery Reperfusion Therapy Series Serine Proteinase Inhibitors Technology Testing Therapeutic Transplantation Vascular Endothelium Vesicle Work antibody-mediated rejection complement 1q receptor delayed graft function digital extracellular vesicles immunogenic inhibitor inhibitor therapy neutrophil organ injury platelet function preservation receptor binding receptor function recruit response success vesicular release

Acute Antibodies Antibody Therapy Apoptotic Autoantibodies Autoantigens Autoimmunity Binding Biopsy Blood Platelets C1q deficiency Cells Chemotactic Factors Chronic Clinical Trials Complement Complement 1q Complement 3a Complement 5a Complement Activation Complement Inactivators Complement component C1r Complement component C1s Complement component C5 Endothelium Generations Goals Human Immune response Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Ischemia Isoantibodies Kidney Transplantation Label Macrophage Mediating Mediator Mus Myeloid Cells NK Cell Activation Natural Killer Cells Organ Organ Transplantation Pathway interactions Patients Pattern recognition receptor Production Publications Recovery Reperfusion Therapy Series Serine Proteinase Inhibitors Technology Testing Therapeutic Transplantation Vascular Endothelium Vesicle Work antibody-mediated rejection complement 1q receptor delayed graft function digital extracellular vesicles immunogenic inhibitor inhibitor therapy neutrophil organ injury platelet function preservation receptor binding receptor function recruit response success vesicular release

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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。