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:
  • 金额:
    $ 48.47万
  • 依托单位:
  • 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

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

项目成果

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Xunrong Luo其他文献

Xunrong Luo的其他文献

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{{ truncateString('Xunrong Luo', 18)}}的其他基金

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:
    10467170
  • 财政年份:
    2022
  • 资助金额:
    $ 48.47万
  • 项目类别:
Therapeutics Development Core (Core B)
治疗开发核心(核心B)
  • 批准号:
    10203939
  • 财政年份:
    2018
  • 资助金额:
    $ 48.47万
  • 项目类别:
Therapeutics Development Core (Core B)
治疗开发核心(核心B)
  • 批准号:
    10460933
  • 财政年份:
    2018
  • 资助金额:
    $ 48.47万
  • 项目类别:
Determinants of donor-specific T cell tolerance in kidney transplantation in non-sensitized recipients
非致敏受者肾移植中供体特异性 T 细胞耐受的决定因素
  • 批准号:
    10622059
  • 财政年份:
    2017
  • 资助金额:
    $ 48.47万
  • 项目类别:
Modeling concurrent cytomegalovirus infection and transplantation tolerance
模拟巨细胞病毒并发感染和移植耐受
  • 批准号:
    9240574
  • 财政年份:
    2016
  • 资助金额:
    $ 48.47万
  • 项目类别:
Modeling concurrent cytomegalovirus infection and transplantation tolerance
模拟巨细胞病毒并发感染和移植耐受
  • 批准号:
    9028961
  • 财政年份:
    2016
  • 资助金额:
    $ 48.47万
  • 项目类别:
Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy
用于细胞替代疗法的蛋白质释放微孔支架
  • 批准号:
    9302428
  • 财政年份:
    2010
  • 资助金额:
    $ 48.47万
  • 项目类别:
Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy
用于细胞替代疗法的蛋白质释放微孔支架
  • 批准号:
    8886518
  • 财政年份:
    2010
  • 资助金额:
    $ 48.47万
  • 项目类别:
ECDI Coupled Cells for Tolerance in Allogeniec Islet Cell Transplantation for T1D
ECDI 偶联细胞在 T1D 异体胰岛细胞移植中的耐受性
  • 批准号:
    8001130
  • 财政年份:
    2010
  • 资助金额:
    $ 48.47万
  • 项目类别:
Clinical Islet Transplantation at Northwestern
西北大学临床胰岛移植
  • 批准号:
    7941899
  • 财政年份:
    2009
  • 资助金额:
    $ 48.47万
  • 项目类别:

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同种异体抗原诱导的 Treg 细胞疗法在大鼠肺移植中诱导操作耐受
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cDC1同种异体抗原诱导心脏同种异体移植物存活的要求和机制
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    10744193
  • 财政年份:
    2022
  • 资助金额:
    $ 48.47万
  • 项目类别:
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cDC1同种异体抗原诱导心脏同种异体移植物存活的要求和机制
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  • 财政年份:
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    2019
  • 资助金额:
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  • 项目类别:
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通过抑制肠道内同种抗原的呈现来预防 GVHD
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