Acute Antibody Mediated Kidney Allograft Rejection

急性抗体介导的同种异体移植肾排斥反应

基本信息

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
项目类别：
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

项目摘要

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部署是消除移植中供体反应性T细胞的常见策略收件人。但是，记忆T细胞对耗竭更具耐药性，并且与急性有关用多克隆兔抗胸腺细胞球蛋白（ATG）或抗 - CD52 mab。了解在淋巴细胞移植中重构的T细胞的机制和组成因此，接受者对于合理使用淋巴疗法和改善其移植物的合理使用至关重要效率。我们研究的最终目的是开发方法，以最大程度地减少稳态扩展和将平衡转移到胸腺波西斯，从而避免过度免疫抑制。在以前的资金中循环，我们在小鼠心脏同种批模型中使用了鼠ATG模拟（MATG）来确定体内平衡整个T细胞室的重建是由抗部署的内存CD4+ T细胞驱动的和CD40/CD154途径。而B细胞与T细胞之间的同源TCR-PMHC相互作用是我们将移植后注射和B细胞衍生的细胞因子IL-1β，IL-6和IL-27确定为钥匙支持稳态T细胞恢复的因素。我们的初步数据表明通过模式发出信号识别受体TLR4，TLR9和巨噬细胞诱导的C型讲座（Mincle或Clec4e）需要启动促炎细胞因子的B细胞产生。我们进一步确定了先天的边缘区（MZ）B 细胞充当淋巴细胞减少受体中移植后感染的初始传感器。遗传缺陷或 MZ B细胞的特定定义明显延迟了MATG治疗的心脏同种氏菌受体中的T细胞重建。我们假设在淋巴时通过移植引起的炎症促进了快速T细胞重组。移植物释放的潮湿激活B细胞以秘密促炎细胞因子进一步扩增B细胞活化并直接增强T细胞增殖。特别是，通过C型激活的MZ B细胞凝集素受体和TLR作为移植后注射后促进促炎的初始传感器卵泡B细胞的功能。因此，记忆T细胞的体内稳态恢复并确保同种异体移植通过最大程度地减少潮湿信号传导或靶向MZ B细胞激活和功能，可以减少排斥。我们将以两个具体的目的检验这一假设：目标1。测试Mz B细胞作为移植的主要传感器的作用淋巴细胞减少受体的组织损伤。目的2。调查C型讲座接收器的机制 MINCLE促进MATG淋巴后B细胞促炎功能。拟议的研究将机械地剖析同种异体移植的炎症途径缺血/再灌注损伤推动了抗部署记忆T细胞的快速重建。基于这些见解，我们将测试几种临床相关方法抑制致病性恢复的有效性供体反应性记忆T细胞和ATG治疗的受体中延长心脏同类生存。