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 1

Switch from acute to chronic antibody-mediated kidney allograft rejection in the absence of recipient myeloperoxidase-producing cells.

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Switch from acute to chronic antibody-mediated kidney allograft rejectio...
(A) Complete MHC-mismatched A/J (H-2a) kidney allografts were transplanted into groups of 6 B6.CCR5–/– or 5 B6.CCR5–/–MPO–/– (H-2b) mice. Native kidney nephrectomy was performed on day 4 after transplant. Survival of kidney grafts was followed by daily examination of animal health and confirmed by histopathologic evaluation of harvested grafts. Median survival time was day 22 in B6.CCR5–/– recipients and day 47 in B6.CCR5–/–MPO–/– recipients. *P < 0.002, Kaplan-Meier survival curves with log-rank statistics. (B) Sera from B6.CCR5–/– and B6.CCR5–/–MPO–/– recipients of A/J kidney grafts was obtained from individual recipients at the indicated times after transplant, and the titer of donor-reactive antibody (DSA) was determined. Data indicate mean titer for each graft recipient group ± SEM. (C) H&E staining of kidney isograft and allograft sections to assess of graft injury on day 14 after transplant. Consistent with histopathology of acute ABMR, margination of mononuclear cells into peritubular capillaries and infiltration into the tubules (white arrowheads) is observed in allografts from B6.CCR5–/– recipients, and there is a marked decrease of this infiltration in allografts from B6.CCR5–/–MPO–/– recipients. Allografts from both groups of recipients have DSA-mediated dilation of peritubular capillaries. Sections of C57BL/6 kidney isografts at day 14 are shown for comparison. (D) C4d staining of kidney isograft and allograft sections to assess graft injury on day 14 after transplant. Strong linear staining for C4d is evident in glomerular and peritubular capillaries of the allografts. Marginated mononuclear cells (white arrowheads) are present in dilated capillaries that are lined by endothelial cells with prominent nuclei (black arrowheads). Capillary loops of glomeruli are occluded by leukocytes and thickened (arrows). (E) Gomori’s trichrome, Periodic Schiff’s stain, and C4d staining of typical allograft sections from B6.CCR5–/–MPO–/– recipients on day 48 after transplant indicate typical pathological features of chronic injury, including thickened capillary loops with doubled contours, mononuclear cells occluding capillary lumens, and periglomerular and peritubular fibrosis. Scale bar: 50 μm.