Recipient myeloperoxidase-producing cells regulate antibody-mediated acute versus chronic kidney allograft rejection
Satoshi Miyairi, … , Stanley L. Hazen, Robert L. Fairchild
Satoshi Miyairi, … , Stanley L. Hazen, Robert L. Fairchild
Published June 3, 2021
Citation Information: JCI Insight. 2021;6(13):e148747. https://doi.org/10.1172/jci.insight.148747.
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Research Article Transplantation

Recipient myeloperoxidase-producing cells regulate antibody-mediated acute versus chronic kidney allograft rejection

Abstract

Antibody-mediated rejection (ABMR) continues to be a major problem undermining the success of kidney transplantation. Acute ABMR of kidney grafts is characterized by neutrophil and monocyte margination in the tubular capillaries and by graft transcripts indicating NK cell activation, but the myeloid cell mechanisms required for acute ABMR have remained unclear. Dysregulated donor-specific antibody (DSA) responses with high antibody titers are induced in B6.CCR5–/– mice transplanted with complete MHC-mismatched A/J kidneys and are required for rejection of the grafts. This study tested the role of recipient myeloid cell production of myeloperoxidase (MPO) in the cellular and molecular components of acute ABMR. Despite induction of equivalent DSA titers, B6.CCR5–/– recipients rejected A/J kidneys between days 18 and 25, with acute ABMR, whereas B6.CCR5–/–MPO–/– recipients rejected the grafts between days 46 and 54, with histopathological features of chronic graft injury. On day 15, myeloid cells infiltrating grafts from B6.CCR5–/– and B6.CCR5–/–MPO–/– recipients expressed marked phenotypic and functional transcript differences that correlated with the development of acute versus chronic allograft injury, respectively. Near the time of peak DSA titers, activation of NK cells to proliferate and express CD107a was decreased within allografts in B6.CCR5–/–MPO–/– recipients. Despite high titers of DSA, depletion of neutrophils reproduced the inhibition of NK cell activation and decreased macrophage infiltration but increased monocytes producing MPO. Overall, recipient myeloid cells producing MPO regulate graft-infiltrating monocyte/macrophage function and NK cell activation that are required for DSA-mediated acute kidney allograft injury, and their absence switches DSA-mediated acute pathology and graft outcomes to chronic ABMR.

Authors

Satoshi Miyairi, Daisuke Ueda, Takafumi Yagisawa, Daigo Okada, Karen S. Keslar, Kazunari Tanabe, Nina Dvorina, Anna Valujskikh, William M. Baldwin 3rd, Stanley L. Hazen, Robert L. Fairchild

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Figure 6

Differences in transcripts expressed by NK cells infiltrating kidney allografts from B6.CCR5–/– or B6.CCR5–/–MPO–/– recipients.

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Differences in transcripts expressed by NK cells infiltrating kidney all...
A/J kidney allografts from groups of 2 B6.CCR5–/– or B6.CCR5–/–MPO–/– recipients were harvested on day 15 after transplant and were digested to obtain single-cell suspensions. Aliquots were stained with fluorochrome-labeled monoclonal antibody and analyzed by flow cytometry to identify the CD3–NK1.1+DX5+ NK cells that were then purified by flow sorting, and RNA from whole-cell lysates was analyzed by the NanoString nCounter platform using the Mouse PanCancer Immune Profiling panel. (A) A heatmap was generated from the top differentially expressed genes in NK cells isolated from allografts from B6.CCR5–/– or B6.CCR5–/–MPO–/– recipients. (B) Volcano plots indicate upregulated and downregulated genes expressed by purified NK cells in allografts from B6.CCR5–/– or B6.CCR5–/–MPO–/– recipients. Open gray circles represent transcripts that are not changed between the 2 groups; solid black circles indicate DEGs with P < 0.05, 2-tailed t test; solid blue circles indicate DEGs with P < 0.01, 2-tailed t test; solid red circles indicate DEGs with P < 0.001, 2-tailed t test. The most highly significant DEGs are labeled on the plots. (C) KEGG analyses of biological pathways from differentially expressed genes in the NK cells infiltrating allografts from the 2 recipient groups.