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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：
10467170
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/10467170
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 Mediating Mediator of activation protein 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 base chemokine design efficacy testing experience imaging study innovation insight intravital microscopy isoimmunity kidney allograft kidney imaging macrophage 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病的方法受到供体器官的严重限制短缺。加剧这种短缺的是塑造早期同种异体肾移植的关键因素的主要知识差距炎症，进而影响随后的同种免疫。我们的初步研究表明，供体肾脏由移植肾带到受体的常驻巨噬细胞在介导早期同种异体移植肾炎症。具体来说，在移植后不久，这些供体肾脏常驻巨噬细胞增殖旺盛，数量增加，促进移植物迅速浸润受体巨噬细胞。移植物浸润的巨噬细胞反过来产生大量的趋化因子 CCL8，与移植肾的急性排斥有关。治疗上，供体耗尽肾移植前肾脏常驻巨噬细胞导致受者流入量显着减少巨噬细胞及其 CCL8 的产生。这种干预导致了卓越的功能即使在长时间冷缺血的情况下也能进行移植肾，并促进无免疫抑制同种异体移植物的长期存活。这些观察结果使我们推测供体肾脏驻留巨噬细胞通过招募和激活受体巨噬细胞来严格协调早期移植物炎症，然后以 CCL8 依赖性方式促进移植同种免疫。因此，这里有一个潜在的治疗机会的目的是阻断供体肾常驻巨噬细胞和/或 CCL8 信号传导，以抑制早期移植物炎症并促进移植耐受。在这个新的 R01 应用程序中，我们提出了两个具体目标：1) 确定供体肾常驻巨噬细胞促进早期同种异体移植物炎症的机制。这一目标将还测试了针对这些机制减少移植物炎症和扩大利用的功效冷缺血时间较长的供肾； 2) 确定供肾居民的机制巨噬细胞促进同种免疫。这一目标还将测试针对这些机制抑制的功效同种免疫并促进临床上可行的移植耐受诱导。我们经验丰富的团队研究人员包括PI罗博士，他是移植免疫生物学专家，将指导所有免疫学研究小鼠肾移植模型的研究，以及活体组织成像专家沉博士的共同指导，他将指导供体肾脏驻留巨噬细胞与移植物浸润受体相互作用的所有成像研究巨噬细胞。我们的最终目标是确定供体肾脏驻留巨噬细胞在促进早期同种异体肾移植炎症和肾移植同种免疫，并设计临床可行的疗法靶向该细胞群以增强短期同种异体肾移植功能和长期同种异体肾移植功能生存。