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

• 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
• 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

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.

肾移植作为终末期肾病的治疗方法受到供体器官的严重限制 短缺对早期肾移植关键因素的认识不足加剧了这种短缺 炎症，这反过来又影响随后的同种异体免疫。我们的初步研究表明捐赠的肾脏 由移植肾带给受体的驻留巨噬细胞在介导早期 移植肾炎症具体来说，在移植后的第一时间，这些捐赠者的肾脏 常驻巨噬细胞增殖旺盛，数量增加，并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 CCL 8与移植肾的急性排斥反应有关。治疗上，供体耗竭 肾移植前肾内巨噬细胞导致受体流入显著减少 巨噬细胞及其CCL 8的产生。这种干预导致了神经系统的上级功能， 即使在长时间冷缺血的情况下，移植的肾也是如此，并且促进无免疫抑制 同种异体移植物的长期存活率。这些观察结果使我们假设供体肾中的巨噬细胞 通过受体巨噬细胞的募集和激活来关键地协调早期移植物炎症， 以CCL 8依赖性方式促进移植同种异体免疫。因此，一个潜在的治疗机会 阻断供体肾驻留巨噬细胞和/或CCL 8信号传导以抑制早期移植物炎症， 促进移植耐受性。在这个新的R 01应用程序中，我们提出了两个具体目标：1）确定 供体肾驻留巨噬细胞促进早期移植物炎症的机制。这一目标将 还测试了靶向这些机制以减少移植物炎症和扩大 供肾冷缺血时间延长; 2）确定供肾驻留的机制 巨噬细胞促进同种免疫。这一目标还将测试靶向这些机制以抑制 同种免疫和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，一位移植免疫生物学专家，他将指导所有免疫学研究。 在小鼠肾移植模型中的研究，以及共同研究者沈博士，活组织成像专家，他将指导 供体肾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驻留巨噬细胞在促进早期移植中的作用。 肾移植炎症和肾移植同种免疫，并设计临床可行的治疗方法 靶向该细胞群以增强短期肾移植功能和长期肾移植 生存