Acute Humoral Rejection of Renal Allografts

描述（由申请人提供）：目前的免疫抑制已降低了肾移植急性细胞排斥反应的发生率。然而，急性体液性排斥反应（AHR）在肾移植患者的发病率越来越多的观察，是特别难以治疗。抗体介导的机制，造成肾移植损伤和损失仍然知之甚少。由于缺乏动物模型来研究供体特异性抗体反应和随后的同种异体移植物损伤的发展，对这些机制的研究受到阻碍。缺乏合适的模型也阻碍了抑制抗体介导的移植物急性和慢性移植病理学的策略的设计。这个新项目的长期目标是更清楚地了解AHR期间移植肾损伤的炎症机制。该计划包括三个既定的和互动的研究人员，他们将利用肾移植小鼠模型来解决T细胞致敏如何影响同种异体移植反应性抗体的产生，并确定抗体介导的移植物损伤机制，导致急性排斥反应或肾移植物间质纤维化的发展。项目1将研究移植物反应性抗体诱导的中性粒细胞浸润和活化对急性移植物损伤的影响，以及不同MHC差异的肾移植物间质纤维化的发展。项目2将研究其他先天性介质，血小板和补体，在介导肾移植物损伤中的作用，以响应抗体结合到移植物内皮。项目3将确定供体抗原特异性记忆性T辅助细胞对供体反应性抗体反应产生的影响，重点是诱导抗体的特异性和亲和力的变化。这些相互交织的项目的结果将提供一系列的致病事件发生下游抗体结合到移植物内皮细胞的新见解。重要的是，这些研究将测试新的策略，以防止产生供体反应性抗体和抗体介导的肾移植物中的急性损伤以及间质纤维化的发展。 相关性：目前免疫抑制的使用已经降低了T淋巴细胞介导的肾移植排斥反应的发生率，但是由与移植物结合的抗体介导的排斥反应仍然是导致移植物损失的问题。本计画将利用小鼠模型来研究移植肾损伤及移植反应性抗体所诱发的排斥反应的机制，并将测试预防此损伤的新策略。 项目1： 肾移植中抗体诱导的神经组织病理学 项目负责人：费尔柴尔德，R 项目1描述（由申请方提供）：导致移植物损伤和损失的抗体介导机制仍知之甚少。由于缺乏合适的动物模型来研究供体特异性抗体应答启动和增加时同种异体移植物损伤的发展，对这些机制的研究受到阻碍。在大多数情况下，研究急性体液性排斥反应的模型使用移植物反应性抗体的转移或用供体细胞致敏受体，这也引发供体反应性T细胞群。我们最近报道了一种新的模型抗体介导的排斥反应的肾移植在CCR 5-/-受体的供体特异性抗体的滴度在CCR 5缺陷的受体几乎是20倍高于野生型受体和移植物排斥反应的特点是急性体液性排斥反应在临床移植观察。在CCR 5缺陷动物中，肾同种异体移植物在第10天至第20天之间被排斥，伴有C3 d的重度沉积、肾小管周围水肿和中性粒细胞浸润。这些和我们的初步结果使我们提出了一个假设，即抗体介导的肾移植物排斥反应的关键机制是移植物中中性粒细胞的诱导浸润和活化，这直接导致移植物组织损伤并增加受体抗体反应的靶抗原。这一假设将在三个具体目标中得到检验。在具体目标1中，我们将直接测试中性粒细胞在移植物组织病理学中的作用，所述移植物组织病理学由CCR 5-/-受体中不同MHC差异的肾同种异体移植物排斥反应中的特异性抗体膨胀。在特定目标2中，我们将测试这种中性粒细胞介导的组织损伤对不同MHC差异的同种异体肾移植物诱导的抗体库的作用。在最后的具体目标中，我们将使用B细胞耗竭策略来测试限制供体特异性抗体与肾移植物相互作用对急性组织损伤发展以及间质纤维化发展的影响，这些病理影响肾移植物存活的即时功能和长期结果。这些研究将为供体反应性抗体与同种异体移植物内皮细胞结合后诱导的病理学机制提供新的见解。 相关性：由结合到移植物的抗体介导的肾移植排斥仍然是引起移植物功能障碍和损失的问题。本研究将利用一种新的小鼠模型来研究移植物反应性抗体诱导的机制，该机制介导急性或慢性肾移植损伤，导致肾移植物丢失

DESCRIPTION (provided by applicant): Current Immunosuppression has decreased the incidence of acute cellular rejection of renal allografts. However, the incidence of acute humoral rejection (AHR) in renal transplant patients is increasingly observed and is particularly difficult to treat. Antibody mediated mechanisms causing renal graft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of animal models to study the development of donor-specific antibody response and subsequent allograft injury. The absence of appropriate models has also hindered the design of strategies to inhibit antibody-mediated graft acute and chronic graft pathology. The long-term goal of this new program is to provide a clearer understanding of inflammatory mechanisms underlying renal allograft injury during AHR. This program comprises three established and interactive investigators who will utilize mouse models of kidney transplantation to address how T cell sensitization impacts allograft reactive antibody production and to identify mechanisms of antibody mediated graft injury leading to either acute rejection or to the development of interstitial fibrosis in the renal allograft. Project 1 will study the impact of graft-reactive antibody induced neutrophil infiltration and activation on acute graft injury and the development of interstitial fibrosis in renal allografts with varying MHC disparities. Project 2 will investigate the role of other innate mediators, platelets and complement, in mediating renal allograft injury in response to antibody binding to the graft endothelium. Project 3 will determine the impact of donor-antigen specific memory T helper cells on the generation of the donor-reactive antibody response, focusing on changes in the specificities and affinities of the antibodies induced. The results of these intertwined projects will provide novel insights into the series of pathogenic events occurring down-stream from antibody binding to the graft endothelium. Importantly, these studies will test novel strategies to prevent generation of donor-reactive antibody and antibody mediated acute injury in renal allografts as well as the development of interstitial fibrosis. RELEVANCE: The use of current immunosuppression has decreased the incidence of T lymphocyte mediated rejection of renal transplants but rejection mediated by antibodies that bind to the graft continues to be a problem in causing graft loss. This project will utilize mouse models to investigate mechanisms of kidney graft injury and rejection induced by graft-reactive antibody and will test novel strategies to prevent this injury. PROJECT 1: Title: - Antibody Induced Neutrophil Tissue Pathology in Renal Allografts Project Leader: Fairchild, R PROJECT 1 DESCRIPTION (provided by applicant): Antibody mediated mechanisms leading to graft injury and loss remain poorly understood. Investigation into these mechanisms is hampered 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-mediated rejection of renal allografts in CCR5-/- recipients where the titers of donor specific antibody in CCR5-deficient recipients were almost 20-fold higher than in wild-type recipients and graft rejection was characteristic of acute humoral rejection 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 infiltration. These and our preliminary results have led us to propose the hypothesis that a key mechanisms 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 tissue pathology inflated by specific antibodies in the rejection of renal allografts of varying MHC disparities in the CCR5-/- recipients. In Specific Aim 2 we will test the role of this neutrophil mediated tissue damage on the repertoire of antibodies 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 interstitial fibrosis, pathologies that impact the immediate function and long-term outcome of renal allograft survival. These studies will provide novel insights into mechanisms underlying the pathologies induced following donor-reactive antibody binding to the allograft endothelium. RELEVANCE: Rejection of renal transplants mediated by antibodies that bind to the graft continues to be a problem in causing graft dysfunction and loss. This project will utilize a novel mouse model to investigate graft-reactive antibody induced mechanisms that mediate the acute or chronic kidney graft injury that causes the loss of kidney transplants