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.
Highlights
Antibody-mediated rejection (ABMR) continues to be an important cause of kidney graft injury and failure in patients transplanted to correct end-stage kidney disease [1,2,3]
Since MPO is a primary inflammatory mechanism expressed by activated myeloid cells during tissue injury, the survival of complete MHC-mismatched A/J kidney grafts in B6.CCR5–/– and B6.CCR5–/–MPO–/– recipients was compared
Examination of allografts harvested from B6.CCR5–/– and B6.CCR5–/–MPO–/– recipients on day 14 after transplant as donor-specific antibody (DSA) was nearing peak titers indicated diffuse C4d staining on glomerular and peritubular capillaries with the characteristic microvascular changes of dilated peritubular capillaries and marginated intracapillary monocytes in allografts from both sets of recipients (Figure 1, C and D), pathological findings that parallel those reported in clinical ABMR [2]
Summary
Antibody-mediated rejection (ABMR) continues to be an important cause of kidney graft injury and failure in patients transplanted to correct end-stage kidney disease [1,2,3]. MPO plays a critical role in host defense to pathogens, including bacteria and yeast, in the pathogenesis of antineutrophil cytoplasmic antibody– associated (ANCA-associated) vasculitis, and it can promote the development of chronic kidney and lung disease, cardiac infarction, and atherosclerosis [23,24,25,26,27,28,29,30] Despite this key role in tissue pathology, the role of MPO during donor-reactive immune responses to allografts, the myeloid cell margination of tubular capillaries during ABMR of kidney grafts, has not been investigated
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