Mechanisms of alloantibody production following renal transplantation

肾移植后同种抗体产生的机制

• 批准号: 10551197
• 负责人: Anna Valujskikh
• 金额: $ 59.68万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-22 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551197
• 关键词: Acute; Address; Affect; Affinity; Alloantigen; Allografting; Anatomy; Animals; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Blood; CD80 Antigens; Cadaver; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Maturation; Cell physiology; Cells; Cellular biology; Chronic; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Data; Endothelial Cells; Endothelium; Epithelial Cells; Generations; Histocompatibility Antigens Class II; Human; Immune; Immunoglobulin Class Switching; Impairment; Inflammation; Inflammatory; Injury; Investigation; Ischemia; Isoantibodies; Kidney Transplantation; Knowledge; Ligands; Location; Lymphocyte Activation; MHC Class II Genes; Mediating; Mus; Natural Immunity; Organ Donor; Organ Transplantation; Outcome; Pathogenicity; Patients; Prevention; Production; Reperfusion Injury; Risk; Risk Factors; Role; Series; Signal Transduction; Source; Spleen; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Transplant Recipients; Transplantation; Vascularization; adaptive immune response; adaptive immunity; antibody-mediated rejection; assault; chemokine; cytokine; exosome; extracellular vesicles; graft failure; high risk; improved outcome; inhibiting antibody; isoimmunity; kidney allograft; mortality; mouse model; pathogen; post-transplant; receptor; response; targeted treatment; tissue injury; trafficking

ABSTRACT Acute and chronic antibody-mediated rejection (AMR) is a serious threat to the survival and function of transplanted organs. The current options for AMR prevention and treatment are limited by the incomplete understanding of the mechanisms underlying donor specific alloantibody (DSA) generation and pathogenic functions. Whereas the production of high affinity isotype-switched DSA is typically associated with germinal center formation by follicular B cells, the contribution of marginal zone (MZ) B cells to anti-donor responses following transplantation has not been previously addressed. Our preliminary studies identify MZ B cells as important players in orchestrating DSA responses and warrant detailed investigation of this B cell subset with an ultimate objective of reducing humoral alloimmunity in transplant recipients. Prolonged cold ischemia storage (CIS) of donor allografts and ensuing ischemia/reperfusion injury (IRI) remain among leading risk factors for poor transplant outcome. Using a mouse model of kidney transplantation in which allografts are subjected to 6 h CIS, we found that posttransplant inflammation specifically augments generation of class II-reactive DSA that mediate allograft glomerular injury. These findings are highly relevant to clinical studies revealing correlations between longer cold ischemia time, anti-class II DSA and late AMR in renal transplant patients. However, the mechanisms by which posttransplant inflammation affects generation of pathogenic class II DSA and the very source of donor class II antigens for B cell activation are poorly defined. Based on our preliminary data, we hypothesize that IRI amplifies class II DSA production through the following steps: 1) IRI up-regulates MHC class II expression on donor endothelial cells (EC) and EC release of class II containing extracellular vesicles (EEVs); 2) spleen MZ B cells rapidly acquire circulating EEVs, produce early DSA and facilitate further DSA production by FO B cells; and, 3) in addition to donor alloantigens, MZ B cell activation is initiated and enhanced by DAMPs carried by graft-derived EVs as well as by systemic effects of IRI. Therefore, targeting MZ B cell trafficking, activation and functions will inhibit generation of pathogenic class II DSA and improve outcome of renal allografts subjected to prolonged CIS. We will test this hypothesis in three Specific Aims: Aim 1. To test whether ischemia/reperfusion injury (IRI) augments class II DSA by enhancing endothelial extracellular vesicles (EEV) generation. Aim 2. To test the role of MZ B cells in DSA production following renal transplantation. Aim 3. To investigate the contribution of MZ B cells in the generation of pathogenic class II DSA after prolonged cold ischemia storage of renal allografts. The proposed studies will fill several gaps in current knowledge of humoral alloimmune responses to vascularized organ transplants and identify potential targets of therapeutic intervention to inhibit antibody- mediated rejection.

抽象的 急性和慢性抗体介导的排斥反应（AMR）严重威胁着机体的生存和功能。 移植的器官。目前 AMR 预防和治疗的选择受到不完整的限制 了解供体特异性同种抗体 (DSA) 生成和致病机制 功能。而高亲和力同种型转换 DSA 的产生通常与生发相关 滤泡 B 细胞的中心形成、边缘区 (MZ) B 细胞对抗供体反应的贡献 先前尚未解决移植后的问题。我们的初步研究确定 MZ B 细胞为 协调 DSA 反应的重要参与者，并需要对这个 B 细胞子集进行详细研究 最终目标是减少移植受者的体液同种免疫。 供体同种异体移植物的长期冷缺血储存（CIS）和随之而来的缺血/再灌注损伤（IRI）仍然存在 移植结果不佳的主要危险因素之一。使用小鼠肾移植模型，其中 同种异体移植物接受 6 小时 CIS，我们发现移植后炎症特别增加了世代 介导同种异体移植肾小球损伤的 II 类反应性 DSA。这些发现与临床高度相关 研究揭示了较长的冷缺血时间、抗 II 类 DSA 与肾脏晚期 AMR 之间的相关性 移植患者。然而，移植后炎症影响生成的机制 致病性 II 类 DSA 和用于 B 细胞激活的供体 II 类抗原的来源尚不清楚。 根据我们的初步数据，我们假设 IRI 通过以下方式扩大 II 类 DSA 产量 步骤： 1) IRI 上调供体内皮细胞 (EC) 上 MHC II 类表达以及 EC II 类释放 含有细胞外囊泡（EEV）； 2）脾脏MZ B细胞快速获得循环EEV，早期产生 DSA 并促进 FO B 细胞进一步生产 DSA； 3) 除了供体同种异体抗原外，MZ B 细胞 移植物来源的 EV 携带的 DAMP 以及 IRI 的全身效应可启动和增强激活。 因此，针对 MZ B 细胞的运输、激活和功能将抑制致病性 II 类细胞的产生 DSA 并改善接受长期 CIS 的同种异体肾移植物的结果。我们将分三步检验这个假设 具体目标： 目标 1. 测试缺血/再灌注损伤 (IRI) 是否通过增强内皮细胞功能来增强 II 类 DSA 细胞外囊泡（EEV）的产生。目标 2. 测试肾移植后 MZ B 细胞在 DSA 产生中的作用 移植。目标 3. 研究 MZ B 细胞在致病性 II 类 DSA 生成中的贡献 同种异体肾移植物长期冷缺血保存后。 拟议的研究将填补当前体液同种免疫反应知识的几个空白 血管化器官移植并确定治疗干预的潜在目标以抑制抗体- 介导的排斥反应。