Complement regulates macrophage and platelet function in kidney transplants

摘要 器官恢复、缺血再灌注和抗体介导的补体激活的可能性 排斥(AMR)是公认的。因此，许多补体的治疗性抑制剂已经被 在治疗AMR方面进行了开发和测试。末端补体成分C5的抑制剂等 最近，经典通路的第一个组成部分c1得到了最广泛的测试。广泛的证据 表明C1q作为模式识别受体(PRR)与凋亡细胞结合，并介导非 巨噬细胞清除炎症。事实上，C1q缺乏的患者和小鼠并不清除凋亡细胞 并发展出鲜艳的自身免疫力。值得注意的是，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，移植肾功能延迟造成的损伤已经通过使用 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保持不变。 这些结果提出了一个明显的问题：C1inh是否有效，因为它截断了补体级联和 减少下游炎症介质的产生或C1inh起作用，因为它保持C1q不变 来调节巨噬细胞和表达C1q受体的细胞？当然，这些并不是相互排斥的。 对C5a在抗体诱导的炎症中的作用有更多的了解。C5a是一种强有力的化学诱导剂。 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 在抗体结合并激活移植物内皮上的补体后，血小板在几分钟内积累。 我们提出的假设是C1q下调而C5a上调炎症反应。 因此，保留C1q功能和抑制C5a功能将降低AMR。我们将对此进行测试 以下3个具体目标中的假设：1)测试C1q作为PRR的能力，以潜在地去除 免疫原性细胞外囊泡在移植后再灌流中的作用及减少同种异体肾移植的诱导 和自身抗体反应。2)检测补体C5a对缺血大鼠中性粒细胞和巨噬细胞功能的影响。 再灌注和慢性AMR。3)检测C5a对急性和慢性AMR患者血小板功能的影响。这些 具体目标包括并增强我们的PPG的共同线索，这些线索侧重于潜在的机制 AMR.这项建议的目的是为合理治疗强化有益的 C1q在移植中的作用及C3a、C5a促炎症作用的调节

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.