Kidney Allograft Recipient Absence of Myeloperoxidase Decreases Donor-Specific Antibody Titers and Attenuates Antibody-Mediated Allograft Rejection

Abstract

Abstract The incidence of antibody-mediated rejection (AMR) in clinical kidney transplants is increasingly observed. We have reported that strong donor-specific antibody (DSA) responses are induced in B6.CCR5−/−mice transplanted with complete MHC mismatched A/J kidney allografts and that NK cells play a critical role in acute injury and graft failure. Since this acute AMR is accompanied by intense macrophage infiltration into the allograft, we tested the role of recipient-derived myeloperoxidase (MPO) production on kidney allograft survival. B6.CCR5−/−and B6.CCR5−/−MPO−/−mice were transplanted with complete MHC mismatched A/J kidney grafts. Allografts were rejected between days 18 and 25 post-transplant in B6.CCR5−/−recipients but not until days 46–54 in B6.CCR5−/−MPO−/− recipients. DSA titers in B6.CCR5−/−MPO−/−recipients were 4–5 fold lower than those induced in the B6.CCR5−/− recipients. There was also a 60% decrease in the number of donor-reactive T cells producing IFN-g in the spleens of the B6.CCR5−/−MPO−/− vs. B6.CCR5−/−recipients on day 7 post-transplant. Despite the extended survival, qPCR analyses indicated slight increases in mRNA encoding TNFa, IL-6 and FasL in kidney allografts on day 14 post-transplant in B6.CCR5−/−MPO−/− vs. B6.CCR5−/−recipients as well as the pro-fibrogenic factors P-selectin and connective tissue growth factor on day 50 post-transplant. These results suggest MPO regulates the magnitude of the DSA and T cell response in kidney transplant recipients and that the decreased DSA titers attenuate acute AMR but induce the indolent development of interstitial fibrosis and glomerular injury that will eventually lead to graft dysfunction and failure at later times.