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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.

摘要