Oxidized-ATP Attenuates Kidney Allograft Rejection By Inhibiting T-Cell, B-Cell, and Macrophage Activity

Abstract

BackgroundExtracellular ATP binds to purinergic receptors and promotes inflammatory responses. We tested whether oxidized ATP (oATP), P2X7 receptor antagonist can attenuate acute kidney allograft rejection.MethodsBrown Norway kidney allografts were transplanted into Lewis recipients. Three groups were defined: oATP (n=8), cyclosporine A (n=6), and no treatment (n=8). On day 7, we assessed kidney allograft survival, function, and rejection characteristics. We further determined T-cell, B-cell, and macrophage response to oATP in vivo and in vitro and examined intragraft inflammatory gene transcripts.ResultsKaplan–Meier survival analyses demonstrated significantly better graft survival rates in oATP and CsA groups compared with no treatment (P<0.05). Similarly, serum creatinine (Scr) and BUN levels were significantly lower in oATP and CsA groups (P<0.05). oATP reduced both T cell–mediated rejection and antibody-mediated rejection, inhibited B-cell and T-cell activation, and downregulated intragraft IL-6 mRNA levels (P<0.0001). In vitro, oATP prevented proliferation in mixed lymphocyte reaction assays, and inhibited macrophage P2X7R activity in a dose-dependent manner.ConclusionsOur findings suggest that oATP mitigates kidney allograft rejection by inhibiting T-cell, B-cell, and macrophage activity and indicate a potential role for the purinergic system and oATP in solid organ transplantation.