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.

项目概要/摘要 导致急性和慢性同种异体移植肾损伤和丢失的抗体介导机制仍然很差 明白了。由于缺乏合适的动物模型来研究这些机制，阻碍了对这些机制的研究。 研究当供体特异性抗体 (DSA) 反应启动时同种异体移植物损伤的发展 增加。我们开发了一种新的同种异体肾移植物抗体介导的排斥反应（AMR）模型 CCR5-/- 受体，其中 DSA 滴度响应于完全 MHC 不匹配的同种异体肾移植物 比野生型受体中引发的结果高 50 倍以上。同种异体肾移植物受到严重排斥 第 17 天至第 22 天期间 CCR5-/- 受体中的抗体反应，伴有 C3d、肾小管周围的大量沉积 水肿、中性粒细胞和巨噬细胞浸润和激活，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 同种异体肾移植物急性和慢性 AMR 的根本原因是中性粒细胞和中性粒细胞的诱导浸润和激活。 移植物中的巨噬细胞，直接引起移植物组织急、慢性损伤，增加靶标 受体抗体反应的抗原。该假设将在三个具体目标上进行检验。具体来说 目标 1 我们将鉴定并测试 MPO 生成细胞在抗体介导的急性排斥反应中的作用 CCR5-/- 受体的同种异体肾移植物。在特定目标 2 中，我们将测试中性粒细胞和巨噬细胞的作用 介导供体 MHC 和自身抗原特异性抗体生成过程中的同种异体移植组织损伤 对同种异体肾移植物的反应。在特定目标 3 中，我们将使用 B 细胞耗竭策略来测试分子 导致抗体介导的间质纤维化和肾小管萎缩的机制 同种异体肾移植物。这些研究将利用抗体介导的急性和慢性同种异体肾移植的新模型 损伤为这些病理背后的机制提供新的见解，这仍然是一个主要问题 损害肾移植的成功。我们预计这些研究的结果将表明新的 治疗目标是抑制或减轻抗体介导的移植物损伤。