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）是对的严重威胁 移植器官。当前预防AMR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）产生和致病性的机制 功能。而高亲和力同种型开关DSA的产生通常与生发有关 卵泡B细胞的中心形成，边缘区（MZ）B细胞对抗抑制反应的贡献 以前尚未解决遵循移植。我们的初步研究将MZ B细胞视为 精心策划DSA响应的重要参与者和保证对此B细胞子集的详细调查 减少移植受体中的体液同种异体性的最终目标。 供体同种异体移植物和随之而来的缺血/再灌注损伤（IRI）的长时间冷缺血储存（CI）仍然存在 在领先的危险因素中，较差的移植结果。使用肾脏移植的小鼠模型 同种异体移植受到6 h顺式的约束，我们发现移植后炎症特异性增强了产生 介导同种异体肾小球损伤的II类反应性DSA的。这些发现与临床高度相关 研究揭示了较长的冷缺血时间，抗阶段II DSA和肾后期AMR之间的相关性 移植患者。但是，移植后炎症影响产生的机制 病原II类DSA和用于B细胞激活的II类抗原的供体的来源很差。 根据我们的初步数据，我们假设IRI通过以下 步骤：1）IRI上调在供体内皮细胞（EC）和II类EC释放的MHC II类表达 包含细胞外囊泡（EEV）； 2）脾脏MZ B细胞迅速获取循环EEV，早期产生 DSA并促进FO B细胞进一步生产DSA； 3）除了供体同种剂，MZ B细胞 由移植衍生的电动汽车以及IRI的全身效应携带的潮湿引发并增强了激活。 因此，靶向MZ B细胞运输，激活和功能将抑制病原II类的产生 DSA和改善接受长时间顺式的肾脏同种异体移植的结果。我们将在三个中检验这一假设 具体目的： 目的1。测试缺血/再灌注损伤（IRI）是否通过增强内皮增强II类DSA 细胞外囊泡（EEV）产生。目标2。测试MZ B细胞在肾脏后DSA产生中的作用 移植。目的3。研究MZ B细胞在致病性II类DSA生成中的贡献 长时间冷缺血储存后，同种异体移植物。 拟议的研究将填补当前对同种异体响应的知识的空白 血管化器官移植并确定治疗干预的潜在靶标，以抑制抗体 - 介导的拒绝。