Antibody Induced Neutrophil Tissue Pathology in Renal Allografts

抗体介导的导致移植物损伤和丢失的机制仍然知之甚少。对…的调查 这些机制由于缺乏适当的动物模型来研究其发生发展而受到阻碍。 随着供者特异性抗体反应的启动和增加，同种异体移植损伤也随之增加。在大多数情况下，模特 应用移植物反应性抗体转移或受体致敏研究急性体液排斥反应 供体细胞也启动了供体反应性T细胞群。我们最近报道了一部小说 CCR5-/-受者肾移植抗体特异性排斥反应模型 CCR5缺陷受体的抗体水平几乎是野生型受体的20倍 移植物排斥反应是临床移植中观察到的急性体液排斥反应的特征。在CCR5中- 缺乏C3d的动物，移植肾在第10至20天内被排斥，并大量沉积C3d， 肾小管周围水肿和中性粒细胞渗入。这些和我们的初步结果使我们提出了 假说抗体介导的移植肾排斥反应的一个关键机制是诱导 中性粒细胞在移植物中的渗透和激活，直接导致移植物组织损伤和增加 受体抗体反应的靶抗原。这一假设将在三个具体目标上得到检验。 在特定目标1中，我们将直接测试中性粒细胞在由特定因素引起的移植物裂缝病理中的作用。 CCR5-/-受体中不同MHC差异的移植肾排斥反应中的抗体。具体而言 目的2我们将测试这种中性粒细胞介导的裂隙损伤在诱导的抗体谱系中的作用。 到不同MHC差异的同种异体肾移植。在最终的具体目标中，我们将使用B细胞耗尽策略 目的：检测限制供者特异性抗体与移植肾相互作用对移植物生长发育的影响。 急性组织损伤以及间质纤维化的发展，影响 移植肾存活率的即刻功能和远期结局。这些研究将为我们提供新的 对供体反应性抗体结合后引起的病理机制的洞察 同种异体内皮细胞。 相关性(请参阅说明)：

Antibody mediated mechanisms leading to graft injury and loss remain pooriy understood. Investigafion into these mechanisms is hampared by the lack of appropriate animal models to study the development of allograft injury as the donor-specific antibody response is initiated and increases. For the most part, models studying acute humoral rejection use either transfer of graft-reactive antibodies or sensitization of recipients with donor cells which also primes donor-reactive T cell populations. We have recently reported a novel model of antibody-meidated rejection of renal allografts in CCR5-/- recipients where the titers of donorspecific anfibody in CCR5-deficient recipients were almost 20-fold higher than in wild-type recipients and graft rejection was characterisfic of acute humoral rejecfion observed in clinical transplants. In CCR5- deficient animals, the renal allografts are rejected between days 10 and 20 with heavy deposition of C3d, peritubular edema and neutrophil infiltrafion. These and our preliminary results have led us to propose the hypothesis that a key mechanims underlying antibody-mediated rejection of renal allografts is the induced infiltration and activation of neutrophils in the grafts which directly causes graft tissue injury and increases the target antigens of the recipient antibody response. This hypothesis will be tested in three specific aims. In Specific Aim 1 we will directly test the role of neutrophils in the graft fissue pathology inflated by specifc antibodies in the rejecfion of renal allografts of varying MHC disparities in the CCR5-/- recipients. In Specific Aim 2 we will test the role of this neutrophil mediated fissue damage on the repertoire of anfibodies induced to renal allografts of varying MHC disparities. In the final specific aim we will use a B cell depletion strategy to test the effect of limiting donor-specific antibody interaction with the renal allograft on the development of acute tissue injury as well as on the development of interstitital fibrosis, pathologies that impact the immediate function and longterm outcome of renal allograft survival. These studies will provide novel insights into mechanisms underlying the pathologies induced following donor-reactive anfibody binding to the allograft endothelium. RELEVANCE (See instructions):