Donor-specific antibody mediates chronic, but not acute, kidney allograft rejection in the absence of natural killer cells

Abstract

Abstract Dysregulated donor-specific antibody (DSA) responses are induced in B6.CCR5−/− mice transplanted with complete MHC mismatched kidney allografts and NK cells play a critical role in acute graft injury and failure. The current study investigated the consequence of high DSA titers on graft outcomes in the presence vs. absence of NK cell activation within the kidney graft. B6.CCR5−/− recipients of complete MHC mismatched A/J allografts or semi allogeneic (A/J x B6)F1 kidney grafts responded with equivalent serum DSA titers that reached peak by day 14 post-transplant. B6.CCR5−/− recipients rejected A/J allografts between days 15–30, whereas B6 isografts and (A/J x B6)F1 semi allogeneic grafts survived past day 65. On day 7 post-transplant NK cell infiltration into A/J allografts was composed of distinct Ly49b+ cell populations expressing low and high levels of NK1.1 and both NK1.1high and NK1.1low cells increased in A/J allografts with time to rejection. In contrast, NK cell infiltration into (A/J x B6)F1 grafts on day 7 post-transplant was composed entirely of NK1.1high cells that decreased to background/isograft numbers thereafter. (A/J x B6)F1 grafts at day 65 post-transplant had severe chronic injury with prominent interstitial fibrosis, glomerulopathy and arteriopathy that was accompanied by gene expression of profibrogenic factors. These results indicate that NK cells synergize with DSA to cause acute kidney allograft failure whereas high titers of DSA in the absence of NK cell activation cannot cause acute antibody-mediated rejection but induce the indolent development of interstitial fibrosis and glomerular injury that leads to graft dysfunction and failure at later times after transplantation.