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
• 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
• 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/10490858
• 关键词: Acute; Antibodies; Antibody Therapy; Apoptotic; Autoantibodies; Autoantigens; Autoimmunity; Binding; Biopsy; Blood Platelets; Cells; Chemotactic Factors; Chronic; Clinical Trials; Complement; Complement 1q; Complement 3a; Complement 5a; Complement Activation; Complement Inactivators; Complement component C5; Endothelium; Generations; Goals; Human; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Ischemia; Isoantibodies; Kidney Transplantation; Label; Mediating; Mediator of activation protein; 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; macrophage; neutrophil; organ injury; platelet function; preservation; receptor binding; receptor function; recruit; response; success; vesicular release

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.

摘要 补体激活在器官恢复、缺血再灌注和抗体介导的 拒绝（AMR）是公认的。因此，许多补体的治疗性抑制剂已经被用于治疗癌症。 在AMR的治疗中开发和测试。末端补体成分C5的抑制剂等 近年来，经典途径的第一组分C1被广泛地研究。大量证据 表明C1 q作为模式识别受体（PRR）发挥作用，其结合凋亡细胞并介导非- 巨噬细胞的炎症清除。事实上，C1 q缺陷患者和小鼠不能清除凋亡细胞 并产生丰富的自身免疫。关于C1 q在移植中的作用知之甚少。 然而，在最近的临床试验中，移植物功能延迟引起的损伤已经通过以下治疗而减少： C1抑制剂（C1 inh），一种丝氨酸蛋白酶抑制剂，可终止补体激活，但保留C1 q完整。 这些结果引出了一个显而易见的问题：C1 inh是否起作用，因为它截断了补体级联反应， 减少下游炎症介质的产生，或者C1 inh起作用，因为它保持C1 q完整 调节巨噬细胞和表达C1 q受体的细胞？当然，这些并不是相互排斥的。 关于C5 a在抗体诱导的炎症中的功能，了解更多。C5 a是一种有效的化学引诱物 以及嗜中性粒细胞和巨噬细胞的激活剂。然而，血小板也表达C5 aR。我们已经证明 血小板在抗体结合并激活移植物内皮上的补体后数分钟内聚集。 我们提出假设，C1 q下调，而C5 a上调炎症反应， 因此，保留C1 q功能和抑制C5 a功能将降低AMR。我们将测试这个 以下3个具体目标的假设：1）测试C1 q作为PRR的功能，以消除潜在的 免疫原性细胞外囊泡在移植后再灌注过程中，并减少异基因 和自身抗体反应。2)测试C5 a对缺血中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C5 a对急性和慢性AMR中血小板功能的影响。这些 具体的目标包含并加强了我们的PPG的共同点，重点是基本机制 AMR。本提案的目标是为合理治疗增强有益的 C1 q在移植中的功能以及C3 a和C5 a的促炎作用的调节。