Innate B cell immunity and antibody-mediated rejection of human kidney allografts

先天 B 细胞免疫和抗体介导的人肾同种异体移植排斥

• 批准号: 9766181
• 负责人: Emmanuel Zorn
• 金额: $ 44.16万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-26 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766181
• 关键词: Antibodies; Antibody-Producing Cells; Apoptotic; Autoantibodies; B-Lymphocytes; Biological Assay; Blinded; Blood; Blood Vessels; Blood capillaries; Cells; Cellular Structures; Chronic; Clinical; Clone Cells; Collection; Complement; Complex; Complication; Data; Deposition; Deterioration; Development; Elements; End stage renal failure; Frequencies; Functional disorder; Human; IgG1; IgG3; Immune; Immunity; Immunoglobulin G; Immunoglobulin M; Immunoglobulin-Secreting Cells; Investigation; Kidney; Kidney Transplantation; Link; Measurement; Mediating; Minor; Mus; Mutant Strains Mice; Noise; Organ Transplantation; Outcome; Pathogenicity; Pathway interactions; Patients; Phenotype; Predictive Factor; Production; Proteinuria; Reaction; Reporting; Research; Role; Sampling; Series; Serum; Source; Specimen; Survival Rate; System; Tissue Grafts; Transplant Recipients; Transplantation; base; clinically relevant; clinically significant; cohort; complement C4d; design; enzyme linked immunospot assay; experimental study; graft failure; in vivo; kidney allograft; monocyte; novel; post-transplant; predictive modeling; prevent; prospective; response; transplant centers; transplant model; treatment choice

Project Summary Transplantation is currently the treatment of choice for a number of end stage kidney diseases. Considerable progress has been made in the past decades to prevent early rejection of kidney grafts. Yet, long-term survival rates remain poor, due presumably to antibody-mediated rejection (ABMR). Although antibodies specific to donor HLA molecules (DSA) indisputably contribute to mechanisms of ABMR, other types of antibodies, especially autoantibodies, have also been implicated. Previous studies from our lab associated natural antibodies (Nabs) reactive to apoptotic cells with ABMR. Moreover, we found that high level of IgG Nabs in pre-transplant serum correlated with long-term graft loss independently of anti-HLA antibodies. Based on this data, we hypothesize that Nabs are important elements in the development of ABMR and subsequently graft loss. Here, we propose to continue these studies by extending our analysis to a larger group of patients treated at other centers. We will also investigate the source of Nabs and characterize the pathogenic potential of these antibodies in vivo. Our experiments will be carried out in 3 aims: Aim-1. To determine whether serum IgG Nabs correlate with ABMR and long-term kidney graft loss. We will carry out a blinded multi-center large-scale assessment of IgG Nabs in pre- and post-transplant serum samples from an extensive cohort of kidney transplant recipients. Serum IgG Nabs measurements will be correlated with donor specific antibodies, other non-HLA antibodies as well as a comprehensive series of clinical parameters including different types of rejection and causes of graft loss. A predictive model will then be built to evaluate the clinical relevance of Nabs levels as a significant factor predicting rejection and graft failure. The synergistic effect between Nabs, DSA and other types of antibodies will also be evaluated. Aim 2. To determine the source of Nabs during ABMR. Using ELISPOT assays we will assess the frequency of IgM and IgG Nabs-producing cells in the blood and graft tissue of kidney transplant recipients and determine whether this frequency correlates with serum Nabs levels and ABMR. We will also attempt to characterize the phenotype of Nabs-producing innate B cells. Aim 3. To verify the pathogenicity of Nabs in vivo. In this aim we will use a mouse aortic transplantation model to study the pathogenicity of IgG Nabs in vivo. Through passive transfer of Nabs and DSA in transplanted mice, we will also investigate the synergistic effect of both types of antibodies. Lastly, we will use a series of mutant mice to investigate the molecules, immune cells and pathways involved in Nabs-mediated vascular rejection.

项目摘要 移植目前是许多终末期肾病的治疗选择。相当大 在过去的几十年中，在预防肾移植的早期排斥方面已经取得了进展。然而，长期生存 率仍然很低，可能是由于抗体介导的排斥反应（ABMR）。虽然抗体特异于 供体HLA分子（DSA）无可争议地有助于ABMR的机制，其他类型的抗体， 尤其是自身抗体也有牵连。我们实验室以前的研究与自然 用ABMR检测与凋亡细胞反应的抗体（Nabs）。此外，我们发现，高水平的IgG Nabs， 移植前血清与长期移植物丢失相关，与抗HLA抗体无关。基于此 根据这些数据，我们假设Nabs是ABMR发展和随后移植的重要因素。 损失在这里，我们建议继续这些研究，将我们的分析扩展到更大的一组接受治疗的患者， 在其他中心。我们还将调查Nabs的来源，并描述这些Nabs的致病潜力。 体内抗体。我们的实验将在3个目标进行： 目标一确定血清IgG Nab是否与ABMR和长期肾移植物丢失相关。我们 将对移植前和移植后血清中的IgG Nab进行盲态多中心大规模评估 来自大量肾移植受者的样本。血清IgG Nabs测量将 与供体特异性抗体、其他非HLA抗体以及一系列广泛的 临床参数包括不同类型的排斥反应和移植物丢失的原因。预测模型将 旨在评估Nabs水平作为预测排斥反应和移植物的重要因素的临床相关性 失败还将评估Nabs、DSA和其他类型的抗体之间的协同效应。 目标二。确定ABMR期间Nab的来源。使用ELISPOT分析，我们将评估 肾移植受者血液和移植物组织中IgM和IgG Nabs产生细胞的频率， 确定该频率是否与血清Nabs水平和ABMR相关。我们还将尝试 表征产生Nabs的先天性B细胞的表型。 目标3。验证Nabs的体内致病性。为此，我们将使用小鼠主动脉移植 模型，以研究IgG Nabs在体内的致病性。通过Nabs和DSA的被动转移， 在移植小鼠中，我们还将研究两种类型的抗体的协同作用。最后，我们将使用 一系列的突变小鼠，以研究参与Nabs介导的免疫应答的分子、免疫细胞和途径。 血管排斥反应