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Donor Kidney Resident Macrophages in Kidney Allograft Early Inflammation and Alloimmunity

肾同种异体移植早期炎症和同种免疫中的供肾驻留巨噬细胞

基本信息

批准号：
10588212
负责人：
Xunrong Luo
金额：
$ 48.47万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588212
关键词：
Acute Alloantigen Allogenic Allografting CCL8 gene Cells Clinical Effector Cell End stage renal failure Equilibrium Fluorescence Genes Goals Graft Rejection Immune Immune Tolerance Immunity Immunobiology Immunologics Immunosuppression Infiltration Inflammation Inflammatory Response Intervention Intestines Ischemia Kidney Kidney Transplantation Knowledge Label Lung Macrophage Mediating Mediator Mus Myeloid-derived suppressor cells Organ Organ Donor Play Population Process Production Proliferating Reactive Oxygen Species Regimen Regulatory T-Lymphocyte Reperfusion Injury Research Personnel Resistance Role Shapes Signal Transduction Solid Suppressor-Effector T-Lymphocytes T-Lymphocyte Target Populations Technology Testing Therapeutic Time Tissue imaging Tissues Transplant Recipients Transplantation Transplantation Tolerance chemokine design efficacy testing experience imaging study innovation insight intravital microscopy isoimmunity kidney allograft kidney imaging multi-photon post-transplant prevent recruit response serial imaging single-cell RNA sequencing targeted treatment therapeutic target transcriptomics transplant model

项目摘要

Access to kidney transplantation as a cure for end-stage renal disease is severely limited by donor organ shortage. Exacerbating this shortage is a major knowledge gap of key factors shaping early kidney allograft inflammation, which in turn impact subsequent alloimmunity. Our preliminary studies suggest that donor kidney resident macrophages brought to the recipient by the transplanted kidney play a major role in mediating early kidney allograft inflammation. Specifically, during the immediate post-transplant period, these donor kidney resident macrophages proliferate robustly and increase in numbers, and promote prompt graft infiltration of recipient macrophages. Graft-infiltrating macrophages in turn produce a significant amount of the chemokine CCL8, which is associated with acute rejection of the transplanted kidney. Therapeutically, depletion of donor kidney resident macrophages prior to kidney transplantation results in a significant reduction of influx of recipient macrophages as well as their production of CCL8. This intervention results in superior function of the transplanted kidney even in setting of prolonged cold ischemia time, and promotes immunosuppression-free long-term allograft survival. These observations led us to hypothesize that donor kidney resident macrophages critically orchestrate early graft inflammation via recruitment and activation of recipient macrophages which then promotes transplant alloimmunity in a CCL8-dependent manner. Thus, a potential therapeutic opportunity here is to block donor kidney resident macrophages and/or CCL8 signaling to inhibit early graft inflammation and to facilitate transplant tolerance. In this new R01 application, we propose two specific aims that will: 1) determine mechanisms by which donor kidney resident macrophages promote early allograft inflammation. This aim will also test the efficacy of targeting these mechanisms to reduce graft inflammation and to expand utilization of donor kidneys with prolonged cold ischemia time; 2) determine mechanisms by which donor kidney resident macrophages promote alloimmunity. This aim will also test the efficacy of targeting these mechanisms to inhibit alloimmunity and to facilitate clinically-feasible transplant tolerance induction. Our experienced team of investigators include the PI Dr. Luo, an expert in transplant immunobiology who will direct all immunological studies in murine kidney transplant models, and the co-I Dr. Shen, an expert in live tissue imaging who will direct all imaging studies of donor kidney resident macrophages interacting with graft-infiltrating recipient macrophages. Our ultimate goal is to define the role of donor kidney resident macrophages in promoting early kidney allograft inflammation and kidney transplant alloimmunity, and to design clinically feasible therapies targeting this cell population for enhancing short-term kidney allograft function and long-term kidney allograft survival.

肾移植作为治疗终末期肾脏疾病的手段受到供体器官的严重限制