Donor Kidney-Resident Passenger Macrophages Promote CCL8-CCR8 Mediated Early Allograft Inflammation
1Medicine, Duke University Medical Center, Durham, NC, 2Duke University Medical Center, Durham, NC, 3Biomedical Engineering, Duke University, Durham, NC, 4Duke Transplant Center, Durham, NC, 5Duke University School of Medicine, Durham, NC
Meeting: 2022 American Transplant Congress
Abstract number: 187
Keywords: Allorecognition, Inflammation, Kidney transplantation, Mice
Topic: Basic Science » Basic Science » 08 - Innate Immunity; Chemokines, Cytokines, Complement
Session Information
Session Name: Innate Immunity, Chemokines, Cytokines, and Complement
Session Type: Rapid Fire Oral Abstract
Date: Sunday, June 5, 2022
Session Time: 5:30pm-7:00pm
Presentation Time: 5:50pm-6:00pm
Location: Hynes Room 309
*Purpose: Early intragraft infiltration of monocytes and macrophages has been associated with acute and chronic allograft rejections. Nevertheless, underlying mechanism remained poorly understood. In the present study, we investigated the role of donor kidney-resident macrophages (KRM) in promoting early intragraft inflammation in a mouse model of kidney transplantation.
*Methods: Kidneys from CD45.2 BALB/c or C57BL/6J (B6) donors were transplanted in to bilaterally nephrectomized CD45.1 congenic B6 recipients. Single cell RNA sequencing and multicolor flow cytometry (FACS) were used for data analysis. For in vivo blockade of chemokine CCL8 or its receptor CCR8, anti-CCL8 or anti-CCR8 monoclonal antibodies were used. In some of the experiments, donors were treated with clodronate liposomes (7 days daily; IP) to deplete kidney-resident macrophages prior to the transplant.
*Results: Single cell transcriptomic analysis revealed increased Ccl8 transcripts in macrophage clusters in kidney allografts undergoing acute rejection on day15 post-transplant. FACS analysis of kidney allografts revealed that donor-KRM persist in the grafts and express CCL8 as early as day1 post-transplant. Infiltrating recipient myeloid cells differentiate into macrophages and start expressing CCL8 by day3 post-transplant. Blockade of CCL8 or its receptor CCR8 drastically prevented intragraft infiltration of CD4, and CD8 T cells and IL-17 expressing γδ T cells on day3 post-transplant. Depletion of donor-KRM prior to the transplant resulted into a significant reduction in Ccl8 expression on day7 post-transplant. Consequently, a marked inhibition was observed in intragraft differentiation of recipient macrophage, and T cell infiltration, including IL-17+ γδ T cells. Interestingly, depletion of donor-KRM resulted into improved allograft-function, histopathology, inflammation and CD8 T cells infiltration on day28 post-transplantation.
*Conclusions: Here, we show for the first-time that CCL8-CCR8 axis plays a critical role in early intragraft inflammation in allogeneic kidney transplantation. Thus, targeting donor kidney-resident macrophages prior to the transplant, specifically with the advancement in ex vivo perfusion circuits during organ preservation, can be an attractive strategy to improve transplant outcomes.
To cite this abstract in AMA style:
Dangi A, Husain I, Natesh N, Shen X, Kwun J, Luo X. Donor Kidney-Resident Passenger Macrophages Promote CCL8-CCR8 Mediated Early Allograft Inflammation [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/donor-kidney-resident-passenger-macrophages-promote-ccl8-ccr8-mediated-early-allograft-inflammation/. Accessed November 21, 2024.« Back to 2022 American Transplant Congress