*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 (ABMR) also requires NK cell activation within the graft that is dependent on myeloid cell production of myeloperoxidase (MPO).

*Methods: Neutrophils are a key source of MPO, this study tested the role of neutrophils on NK cell activation and acute ABMR within complete MHC mismatched A/J kidney grafts in B6.CCR5^-/- recipients.

*Results: B6.CCR5^-/- recipients rejected kidney allografts between days 18-25 whereas rejection in B6.CCR5^-/-MPO^-/- recipients occurred between days 46-54, despite equivalent DSA titers in each recipient group. Treatment of B6.CCR5^-/- recipients with 250 ug neutrophil depleting anti-Ly6G mAb at the time DSA titers reached the midpoint of peak titers on days 10 and 12 post-transplant extended allograft survival beyond > 40 days median survival time. Similar to the absent NK cell activation within kidney allografts from MPO-deficient recipients, neutrophil depletion attenuated NK cell proliferation and expression of CD107a within the allografts and decreased monocyte proliferation and abrogated the appearance of Ly6Chi inflammatory monocytes within the allografts. Histologically, depletion of neutrophils prior to the time peak DSA titers were achieved resulted in decreased Mac2+ macrophage infiltration into the interstitium of kidney allografts in CCR5-deficient recipients on day 14 after transplant and in marked increases in allograft infiltrating monocytes expressing MPO, implicating neutrophil produced MPO in regulating infiltrating leukocyte activation to mediate acute ABMR.

*Conclusions: These results indicate that neutrophil activation to produce MPO within kidney allografts during ongoing ABMR promotes NK cell and myeloid cell activation to mediate acute graft tissue injury leading to rejection.

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