Acute Antibody Mediated Kidney Allograft Rejection

急性抗体介导的同种异体移植肾排斥反应

• 批准号: 10683315
• 负责人: Robert L Fairchild
• 金额: $ 60.75万
• 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: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683315
• 关键词: Acute; Allogenic; Allografting; Animal Model; Antibodies; Antibody Response; Antibody titer measurement; Antithymoglobulin; Attenuated; B-Cell Activation; B-Lymphocytes; Binding; Biopsy; Blood capillaries; C Type Lectin Receptors; C-Type Lectins; CCR5 gene; CDW52 gene; Cell Compartmentation; Cell physiology; Cells; Chronic; Clinical; Data; Deposition; Development; Disease; Endothelial Cells; Endothelium; Equilibrium; Event; Fibrin; Fibrosis; Funding; Genetic; Glomerular Capillary; Goals; Histopathology; Immune; Immunosuppression; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-1 beta; Interleukin-6; Ischemia; Kidney Transplantation; Leukocyte Trafficking; Lymphocyte Depletion; Macrophage; Mediating; Modeling; Monoclonal Antibodies; Mus; Myeloid Cells; NK Cell Activation; Natural Killer Cells; Organ; Oryctolagus cuniculus; Pathogenicity; Pathway interactions; Pattern recognition receptor; Peptide/MHC Complex; Peroxidases; Population; Production; Recovery; Regimen; Reperfusion Injury; Reporting; Resistance; Role; Serum; Signal Transduction; T cell reconstitution; T cell response; T memory cell; T-Cell Proliferation; T-Lymphocyte; TLR4 gene; TNFRSF5 gene; TNFSF5 gene; Testing; Time; Tissue Grafts; Transplant Recipients; Transplantation; Tubular formation; allograft rejection; analog; antibody-mediated rejection; clinically relevant; complement C4d; cytokine; donor-specific antibody; efficacy testing; experience; experimental study; granulocyte; heart allograft; improved; insight; kidney allograft; memory CD4 T lymphocyte; molecular marker; monocyte; mouse model; nephrogenesis; neutrophil; new therapeutic target; novel; post-transplant; prevent; reconstitution; recruit; sensor; success; tissue injury; virtual

ABSTRACT Antibody-mediated lymphocyte depletion is a common strategy to eliminate donor-reactive T cells in transplant recipients. However, memory T cells are more resistant to depletion and have been associated with acute rejection episodes in transplant recipients treated with polyclonal rabbit anti-thymocyte globulin (ATG) or anti- CD52 mAb. Understanding the mechanisms and composition of T cells reconstituted in lymphopenic transplant recipients is thus critical for the rational use of lymphoablative therapies and for improving their graft-prolonging efficacy. The ultimate goal of our studies is to develop approaches that minimize homeostatic expansion and shift the balance towards thymopoiesis, thus avoiding over-immunosuppression. During the previous funding cycle, we used a murine ATG analog (mATG) in a mouse heart allograft model to establish that homeostatic reconstitution of the entire T cell compartment is driven by depletion-resistant memory CD4+ T cells via B cells and CD40/CD154 pathway. While cognate TCR-pMHC interactions between B cells and T cells were dispensable, we identified posttransplant inflammation and B cell-derived cytokines IL-1β, IL-6 and IL-27 as key factors facilitating homeostatic T cell recovery. Our preliminary data indicate that signaling through pattern recognition receptors TLR4, TLR9 and a Macrophage-inducible C-type lectin (Mincle, or Clec4e) is required to initiate B cell production of proinflammatory cytokines. We further identified innate-like marginal zone (MZ) B cells acting as initial sensors of posttransplant inflammation in lymphopenic recipients. Genetic deficiency or specific depletion of MZ B cells markedly delays T cell reconstitution in mATG treated heart allograft recipients. We hypothesize that inflammation induced by transplantation at the time of lymphoablation promotes rapid T cell reconstitution. DAMPs released by the graft activate B cells to secrete proinflammatory cytokines that further amplify B cell activation and directly enhance T cell proliferation. In particular, MZ B cells activated via C-type lectin receptor Mincle and TLRs act as initial sensors of posttransplant inflammation facilitating proinflammatory functions of follicular B cells. Therefore, the homeostatic recovery of memory T cells and ensuing allograft rejection may be decreased by minimizing DAMPs signaling or by targeting MZ B cell activation and functions. We will test this hypothesis in two Specific Aims: Aim 1. To test the role of MZ B cells as primary sensors of graft tissue injury in lymphopenic recipients. Aim 2. To investigate the mechanisms by which C-type lectin receptor Mincle facilitates B cell proinflammatory functions after mATG lymphoablation. The proposed studies will mechanistically dissect how inflammatory pathways triggered by allograft ischemia/reperfusion injury drive rapid reconstitution of depletion-resistant memory T cells. Based on these insights, we will test the efficacy of several clinically relevant approaches for inhibiting recovery of pathogenic donor-reactive memory T cells and prolonging heart allograft survival in ATG treated recipients.

抽象的 抗体介导的淋巴细胞耗竭是消除移植中供体反应性 T 细胞的常见策略 然而，记忆 T 细胞对耗竭的抵抗力更强，并且与急性损伤有关。 用多克隆兔抗胸腺细胞球蛋白（ATG）或抗- 了解淋巴细胞减少移植中 T 细胞重建的机制和组成。 因此，接受者对于合理使用淋巴清除疗法和改善移植物延长时间至关重要 我们研究的最终目标是开发最小化稳态扩张和功效的方法。 将平衡转向胸腺生成，从而避免在先前的资助期间过度免疫抑制。 周期中，我们在小鼠心脏同种异体移植模型中使用了小鼠 ATG 类似物 (mATG)，以建立稳态 整个 T 细胞区室的重建由抗耗竭型记忆 CD4+ T 细胞通过 B 细胞驱动 和 CD40/CD154 途径，而 B 细胞和 T 细胞之间的同源 TCR-pMHC 相互作用。 可有可无，我们确定移植后炎症和 B 细胞源性细胞因子 IL-1β、IL-6 和 IL-27 是关键 我们的初步数据表明，促进稳态 T 细胞恢复的因素是通过模式进行的。 需要识别受体 TLR4、TLR9 和巨噬细胞诱导的 C 型凝集素（Mincle 或 Clec4e） 启动 B 细胞产生促炎细胞因子，我们进一步鉴定了先天样边缘区 (MZ) B。 细胞作为淋巴细胞减少症受者移植后炎症的初始传感器。 MZ B 细胞的特异性消耗显着延迟了 mATG 处理的同种异体心脏移植受者的 T 细胞重建。 我们发现，淋巴消融时移植引起的炎症可促进 T 细胞快速增殖 移植物释放的 DAMP 激活 B 细胞，分泌促炎细胞因子，进一步促进重建。 放大 B 细胞活化并直接增强 T 细胞增殖，特别是通过 C 型活化的 MZ B 细胞。 凝集素受体 Mincle 和 TLR 作为移植后炎症的初始传感器，促进促炎症 因此，记忆 T 细胞的稳态恢复和随后的同种异体移植物的功能。 通过最大限度地减少 DAMP 信号传导或靶向 MZ B 细胞的激活和功能，可以减少排斥反应。 我们将在两个具体目标中检验这一假设： 目标 1. 检验 MZ B 细胞作为移植物主要传感器的作用 目的 2. 研究 C 型凝集素受体的作用机制。 Mincle 在 mATG 淋巴消融后促进 B 细胞促炎功能。 拟议的研究将从机制上剖析同种异体移植物如何触发炎症途径 基于这些，缺血/再灌注损伤驱动抗耗竭记忆T细胞的快速重建。 见解，我们将测试几种临床相关方法抑制致病性恢复的功效 供体反应性记忆 T 细胞和延长接受 ATG 治疗的受者心脏同种异体移植物的存活。