Antibody induced neutrophil and macrophage tissue pathology in renal allografts

同种异体肾移植物中抗体诱导的中性粒细胞和巨噬细胞组织病理学

• 批准号: 9086202
• 负责人: Robert L Fairchild
• 金额: $ 38.23万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086202
• 关键词: Acute; Allogenic; Allografting; Animal Model; Antibodies; Antibody Response; Antigen Targeting; Atrophic; Attenuated; Autoantigens; B-Lymphocytes; Binding; Blood capillaries; CCR5 gene; Cells; Cellular Infiltration; Characteristics; Chronic; Clinical; Complement 3d; Deposition; Development; Dissection; Donor person; Edema; Event; Fibrosis; Generations; Goals; Graft Rejection; Histopathology; Immunosuppression; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Investigation; Kidney; Kidney Transplantation; Life; Macrophage Activation; Mediating; Modeling; Molecular; Myocardium; Neutrophil Activation; Pathology; Peroxidases; Production; Regimen; Role; Serum; T-Lymphocyte; Testing; Tissue Grafts; Tissues; Transplant Recipients; Transplantation; Tubular formation; abstracting; allograft rejection; base; capillary; graft failure; heart allograft; inhibiting antibody; insight; interstitial; kidney allograft; macrophage; neutrophil; new therapeutic target; novel; prevent; research study; response; success

Project Summary / Abstract Antibody-mediated mechanisms leading to acute and chronic renal allograft 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 (DSA) response is initiated and increases. We have developed a novel model of antibody-mediated rejection (AMR) of renal allografts in CCR5-/- recipients where the titers of DSA elicited in response to complete MHC-mismatched renal allografts are >50-fold higher than those elicited in wild-type recipients. The renal allografts are acutely rejected by this antibody response in CCR5-/- recipients between days 17 and 22 with heavy deposition of C3d, peritubular edema, and neutrophil and macrophage infiltration and activation including production of myeloperoxidase (MPO), histopathologic features of rejection that are characteristic of those observed during AMR in clinical transplants. These and our preliminary results have led us to propose the hypothesis that a key mechanism underlying acute and chronic AMR of renal allografts is the induced infiltration and activation of neutrophils and macrophages in the graft, which directly cause the acute and chronic graft tissue injury and increase the target antigens of the recipient antibody response. This hypothesis will be tested in three specific aims. In Specific Aim 1 we will identify and test the role of MPO-producing cells during antibody-mediated acute rejection of renal allografts in CCR5-/- recipients. In Specific Aim 2 we will test the role of neutrophil and macrophage mediated allograft tissue damage in the generation of donor MHC- and autoantigen-specific antibodies in response to renal allografts. In Specific Aim 3 we will use a B cell depletion strategy to test the molecular mechanisms leading to the development of antibody-mediated interstitital fibrosis and tubular atrophy in the renal allografts. These studies will utilize novel models of antibody-mediated acute and chronic renal allograft injury to provide new insights into mechanisms underlying these pathologies that remain a major problem undermining the success of renal transplantation. We anticipate the results of these studies will indicate new therapeutic targets to inhibit or attenuate antibody-mediated graft injury.

项目总结/摘要 抗体介导的机制导致急性和慢性肾移植损伤和损失仍然很差 明白对这些机制的研究由于缺乏适当的动物模型而受到阻碍， 研究供体特异性抗体（DSA）反应启动时同种异体移植损伤的发展， 增大我们建立了一种新的同种异体肾移植抗体介导的排斥反应（AMR）模型， CCR 5-/-受体，其中DSA滴度响应于完全MHC不匹配的肾移植物而引起 比在野生型受体中引发的高>50倍。同种异体肾移植会被这种 CCR 5-/-受体在第17天至第22天之间的抗体应答，C3 d、肾小管周围 水肿、中性粒细胞和巨噬细胞浸润和活化，包括髓过氧化物酶的产生 (MPO)排斥反应的组织病理学特征是临床AMR期间观察到的特征。 移植这些和我们的初步结果使我们提出了一个假设，即一个关键机制 肾移植物的潜在急性和慢性AMR是诱导的中性粒细胞的浸润和活化， 移植物中的巨噬细胞，其直接引起急性和慢性移植组织损伤，并增加靶向 受体抗体反应的抗原。这一假设将在三个具体目标中得到检验。在特定 目的1：我们将鉴定和检测MPO产生细胞在抗体介导的急性排斥反应中的作用。 CCR 5-/-受体的肾移植。在具体目标2中，我们将测试中性粒细胞和巨噬细胞的作用 介导的同种异体移植组织损伤在供体MHC和自身抗原特异性抗体的产生中的作用 对肾移植的反应在特定目标3中，我们将使用B细胞耗竭策略来检测分子水平。 导致抗体介导的胰腺纤维化和肾小管萎缩的机制 肾移植这些研究将利用抗体介导的急性和慢性肾移植的新模型 损伤提供了新的见解，这些病理机制仍然是一个主要问题， 破坏了肾移植的成功我们预计这些研究的结果将表明新的 治疗靶点以抑制或减弱抗体介导的移植物损伤。