Donor Kidney Resident Macrophages in Kidney Allograft Early Inflammation and Alloimmunity

肾移植作为治疗终末期肾脏疾病的方法受到供体器官的严重限制 短缺。加剧这种短缺的是对影响早期肾移植的关键因素的重大认识差距。 炎症，进而影响随后的同种异体免疫。我们的初步研究表明，捐献的肾脏 移植肾带给受者的常驻巨噬细胞在早期调节中起主要作用。 移植肾炎症。具体地说，在移植后的紧接时期，这些捐赠者的肾脏 常驻巨噬细胞旺盛的增殖和数量的增加，并促进移植物迅速渗透 受体巨噬细胞。移植物浸润性巨噬细胞继而产生大量的趋化因子 CCL8，与移植肾的急性排斥反应有关。在治疗上，供体枯竭 肾移植前肾脏滞留巨噬细胞显著减少了受体的涌入 巨噬细胞及其产生的CCL8。这种干预产生了优越的功能 即使在冷缺血时间延长的情况下也能移植肾脏，并促进无免疫抑制 同种异体移植物的长期存活。这些观察使我们假设供者肾脏驻留在巨噬细胞中 通过招募和激活受体巨噬细胞来关键地协调移植物早期炎症，然后 以CCL8依赖的方式促进移植同种免疫。因此，这是一个潜在的治疗机会 是阻断供者肾脏常驻巨噬细胞和/或CCL8信号，以抑制移植物早期炎症和 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 供者肾脏驻留巨噬细胞促进移植物早期炎症的机制。这一目标将 也测试针对这些机制的有效性，以减少移植物炎症和扩大利用 供肾冷缺血时间延长；2)确定供肾驻留的机制 巨噬细胞促进同种异体免疫。这一目标还将测试针对这些机制的有效性，以抑制 同种异体免疫和促进临床可行的移植耐受诱导。我们经验丰富的团队 调查人员包括移植免疫生物学专家罗派博士，他将指导所有免疫学 在小鼠肾脏移植模型方面的研究，以及共同领导的活组织成像专家沈博士 供体肾脏滞留巨噬细胞与移植物浸润性受体相互作用的所有影像研究 巨噬细胞。我们的最终目标是确定供者肾脏驻留巨噬细胞在促进早期 移植肾炎症和移植肾免疫，并设计临床可行的治疗方法 靶向这些细胞群以增强短期移植肾功能和长期移植肾功能 生死存亡。

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.