Recipient Myeloid Cell Myeloperoxidase is Required for Nk Cell Activation During Antibody-Mediated Allograft Rejection

S. Miyairi, N. Dvorina, K. S. Keslar, A. Valujskikh, W. M. Baldwin, R. L. Fairchild

Immunology, Cleveland Clinic Lerner Research Institute, Cleveland, OH

Meeting: 2020 American Transplant Congress

Abstract number: D-335

Keywords: Antibodies, Kidney transplantation, Leukocytes, Rejection

Session Information

Session Name: Poster Session D: B-cell / Antibody /Autoimmunity

Session Type: Poster Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:00pm

Presentation Time: 3:30pm-4:00pm

Location: Virtual

*Purpose: Dysregulated donor-specific antibody (DSA) responses are induced in B6.CCR5-/- mice transplanted with complete MHC mismatched A/J kidney allografts and are required for rejection of the grafts. Acute antibody-mediated rejection (AMR) also requires myeloid and NK cell activation to express effector functions within the graft. This study tested the role of NK cell and myeloid cell interactions on their activation and on allograft survival by using recipients deficient in the myeloid cell-derived enzyme myeloperoxidase (MPO).

*Methods: A/J kidney grafts were transplanted into B6.CCR5-/- or B6.CCR5-/-MPO-/- recipients.

*Results: A/J kidneys transplanted to B6.CCR5-/- recipients rejected between days 18-25 whereas rejection in B6.CCR5-/-MPO-/- recipients occurred between days 46-54, despite equivalent DSA titers in each recipient group. On day 15, graft-infiltrating NK cell activation to proliferate and express CD107a was markedly decreased within allografts in B6.CCR5-/-MPO-/- recipients and was accompanied with decreased graft expression of NK cell activation genes, including SH2D1B1, and IFN-γ and the monocyte/macrophage chemoattractant CCL2. The phenotype of allograft infiltrating myeloid cells was also altered in B6.CCR5-/-MPO-/- recipients and allograft histopathology on day 14 post-transplant indicated marked decreases in Mac-2+ activated macrophages in grafts from B6.CCR5-/-MPO-/- recipients. NanoString analysis of RNA from isolated NK cells infiltrating allografts in CCR5-/- vs. B6.CCR5-/-MPO-/- recipients on day 14 post-transplant indicated completely different transcriptomes, including integrin activation and matrix degradation pathways that were markedly decreased in graft infiltrating NK cells in B6.CCR5-/-MPO-/- vs. those infiltrating allografts in CCR5-/- recipients. Analysis of isolated myeloid cells infiltrating the kidney allografts of the two groups of recipients on day 14 post-transplant also indicated different transcriptomes, including decreased expression of gene pathways involved in matrix degradation, phagocytosis, platelet degranulation, and endosomal TLR signaling by myeloid cells infiltrating allografts in B6.CCR5-/-MPO-/- recipients.

*Conclusions: Overall, the results indicate that expression of MPO is required for activation of kidney allograft-infiltrating NK cells and monocytes/macrophages that promote acute AMR of kidney allografts.

To cite this abstract in AMA style:

Miyairi S, Dvorina N, Keslar KS, Valujskikh A, Baldwin WM, Fairchild RL. Recipient Myeloid Cell Myeloperoxidase is Required for Nk Cell Activation During Antibody-Mediated Allograft Rejection [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/recipient-myeloid-cell-myeloperoxidase-is-required-for-nk-cell-activation-during-antibody-mediated-allograft-rejection/. Accessed November 22, 2024.

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