Acute Humoral Rejection of Renal Allografts

同种异体肾移植物的急性体液排斥

• 批准号: 8081805
• 负责人: Robert L Fairchild
• 金额: $ 162.26万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-08 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081805
• 关键词: Acute; Humoral; Rejection; Renal; Allografts

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

描述(由申请人提供)：目前的免疫抑制已经降低了移植肾急性细胞排斥的发生率。然而，急性体液排斥反应(AHR)在肾移植患者中的发生率越来越高，尤其难以治疗。抗体介导的导致移植肾损伤和丢失的机制仍不清楚。由于缺乏研究供者特异性抗体反应的发展和随后的同种异体移植损伤的动物模型，阻碍了对这些机制的研究。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物病理的策略的设计。这一新计划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。这一计划由三名成熟的互动研究人员组成，他们将利用肾移植的小鼠模型，研究T细胞致敏如何影响移植物反应性抗体的产生，并确定抗体介导的移植物损伤导致急性排斥反应或肾移植物间质纤维化发展的机制。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激活对不同MHC差异的移植肾急性损伤和间质纤维化发展的影响。项目2将调查其他先天介质--血小板和补体--在抗体与移植物内皮结合反应中介导移植肾损伤的作用。项目3将确定供体抗原特异性记忆T辅助细胞对供体反应性抗体反应产生的影响，重点是诱导的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为从抗体结合到移植物内皮的下游发生的一系列致病事件提供新的见解。重要的是，这些研究将测试新的策略，以防止供体反应性抗体的产生和抗体介导的肾移植急性损伤以及间质纤维化的发展。 相关性：目前免疫抑制药物的使用降低了T淋巴细胞介导的肾移植排斥反应的发生率，但通过与移植物结合的抗体介导的排斥反应仍然是导致移植物丢失的一个问题。该项目将利用小鼠模型来研究移植物反应性抗体引起的肾移植损伤和排斥反应的机制，并将测试防止这种损伤的新策略。 项目1： 同种异体肾移植中抗体诱导的中性粒细胞组织病理学 项目负责人：费尔柴尔德，R 项目1描述(由申请人提供)：抗体介导的导致移植物损伤和丢失的机制仍然知之甚少。由于供者特异性抗体反应的启动和增强，缺乏合适的动物模型来研究同种异体移植物损伤的发展，阻碍了对这些机制的研究。在大多数情况下，研究急性体液排斥反应的模型要么使用移植物反应性抗体的转移，要么使用供体细胞对受者进行致敏，这也启动了供体反应性T细胞群。我们最近报道了一种新的CCR5-/-受体肾移植抗体介导的排斥反应模型，在CCR5-/-受体中，供者特异性抗体滴度几乎是野生型受体的20倍，移植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缺乏的动物中，移植肾在第10-20天排斥，C3d大量沉积，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，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上得到检验。在具体目标1中，我们将直接测试中性粒细胞在CCR5-/-受体中不同MHC差异的移植肾排斥反应中由特定抗体夸大的移植物组织病理中的作用。在特定的目标2中，我们将测试这种中性粒细胞介导的组织损伤在不同MHC差异的肾移植诱导的抗体库中的作用。在最终的特定目标中，我们将使用B细胞耗竭策略来测试限制供者特异性抗体与移植肾的相互作用对急性组织损伤和间质纤维化的发展的影响，以及影响移植肾存活的即刻功能和长期结果的病理学。这些研究将为供者反应性抗体与同种异体血管内皮细胞结合后诱导的病理机制提供新的见解。 相关性：通过与移植物结合的抗体介导的肾移植排斥反应仍然是导致移植物功能障碍和丢失的一个问题。该项目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，该机制介导了导致肾移植失败的急性或慢性肾移植损伤。