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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

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、缺血再灌注和抗体介导期间补体激活的潜力排斥（AMR）是众所周知的。因此，许多治疗性补体抑制剂已被开发出来。在 AMR 治疗中开发和测试。末端补体成分 C5 的抑制剂等最近，经典途径的第一个成分 C1 得到了最广泛的测试。大量证据表明 C1q 作为模式识别受体 (PRR) 发挥作用，结合凋亡细胞并介导非- 巨噬细胞清除炎症。事实上，C1q 缺陷的患者和小鼠并不能清除凋亡细胞有效地发展并发展出强大的自身免疫能力。人们对 C1q 在移植中的作用知之甚少。然而，在最近的临床试验中，移植物功能延迟造成的损伤已通过接受治疗而减少。 C1 抑制剂 (C1inh) 是一种丝氨酸蛋白酶抑制剂，可终止补体激活，但使 C1q 保持完整。这些结果引出了一个显而易见的问题：C1inh 是否有效，因为它截断了补体级联并且减少下游炎症介质的产生或 C1inh 起作用，因为它使 C1q 保持完整调节表达 C1q 受体的巨噬细胞和细胞？当然，这些并不是相互排斥的。人们对 C5a 在抗体诱导的炎症中的功能有了更多的了解。 C5a 是一种有效的化学引诱剂以及中性粒细胞和巨噬细胞的激活剂。然而，血小板也表达 C5aR。我们已经证明了抗体结合并激活移植物内皮上的补体后几分钟内血小板就会积聚。我们提出这样的假设：C1q 下调而 C5a 上调炎症反应移植；因此，保留 C1q 功能并抑制 C5a 功能将降低 AMR。我们将测试这个假设有以下 3 个具体目标： 1) 测试 C1q 作为 PRR 的能力，以消除潜在的移植后再灌注期间免疫原性细胞外囊泡并减少同种异体的诱导和自身抗体反应。 2）测试C5a对缺血时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中血小板功能的影响。这些具体目标包含并增强我们 PPG 的共同点，重点关注底层机制 AMR。该提案的目标是为合理治疗增强有益效果提供基础 C1q 在移植中的功能以及 C3a 和 C5a 促炎作用的调节。