# Donor Kidney Resident Macrophages in Kidney Allograft Early Inflammation and Alloimmunity

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $484,686

## Abstract

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.

## Key facts

- **NIH application ID:** 10467170
- **Project number:** 1R01DK132889-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Xunrong Luo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $484,686
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467170

## Citation

> US National Institutes of Health, RePORTER application 10467170, Donor Kidney Resident Macrophages in Kidney Allograft Early Inflammation and Alloimmunity (1R01DK132889-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10467170. Licensed CC0.

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