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 3

Marked differences in myeloid cells infiltrating A/J kidney allografts from B6.CCR5–/– recipients versus B6.CCR5–/–MPO–/– recipients.

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Marked differences in myeloid cells infiltrating A/J kidney allografts f...
A/J kidney allografts were transplanted into groups of 5 B6.CCR5–/– or B6.CCR5–/–MPO–/– mice and harvested on day 15. (A) Representative sections of grafts that were fixed with methanol and stained to detect Mac-2+ macrophages in allografts from B6.CCR5–/– recipients and their decrease in allografts from B6.CCR5–/–MPO–/– recipients. Scale bar: 250 μm. (B) On day 15 after transplant kidney allografts were harvested and digested to obtain single-cell suspensions, and aliquots were stained with fluorochrome-labeled monoclonal antibody for flow cytometry analysis of cells expressing CD11c, Ly6C, F4/80, and Ly6G using the gating strategy indicated. (C) Representative analysis of Ly6C+F4/80– monocytes within the allografts from each recipient group showing the presence of Ly6Chi inflammatory monocytes infiltrating allografts from B6.CCR5–/– recipients and their absence in allografts from B6.CCR5–/–MPO–/– recipients. (D) Recipients were pulsed with BrdU on day 14 after transplant, and on day 15 grafts were harvested, digested, and aliquots of prepared single-cell suspensions were stained with antibodies and graft-infiltrating myeloid cells were gated to analyze the proliferation of Ly6C+F4/80– monocytes and Ly6C–F4/80+ macrophages within the allografts. *P < 0.02, 2-tailed t test.