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 2

Different transcript landscapes in kidney allografts experiencing acute versus chronic ABMR.

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Different transcript landscapes in kidney allografts experiencing acute ...
A/J kidney allografts were transplanted into B6.CCR5–/– or B6.CCR5–/–MPO–/– mice and harvested on day 14 or day 50 as indicated. As a control, C57BL/6 kidney isografts were harvested on day 14 from B6.CCR5–/– recipients. (A) Graft RNA was isolated and analyzed by the NanoString nCounter platform using the Mouse PanCancer Immune Profiling panel, and a heatmap was generated from the top differentially expressed genes. (B and C) Volcano plots indicate increased and decreased genes expressed between (B) allografts from B6.CCR5–/– recipients versus B6.CCR5–/–MPO–/– recipients on day 14 after transplant and (C) allografts from B6.CCR5–/–MPO–/– recipients on day 14 versus those from day 50 after transplant. In both volcano plots, open gray circles represent transcripts that are not changed between the 2 groups; solid black circles indicate differentially expressed genes (DEGs) with P < 0.05, 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. (D) Venn diagrams depicting numbers of shared and unique genes expressed in the allografts from B6.CCR5–/– recipients on day 14 after transplant or from B6.CCR5–/–MPO–/– recipients on day 14 or 50 after transplant compared with genes expressed in isografts on day 14 after transplant.