The incidence of antibody-mediated kidney graft rejection continues to increase. We previously reported that dysregulated donor-specific antibody (DSA) responses were induced in B6.CCR5^-/- mice transplanted with complete MHC mismatched A/J kidney allograft and that NK cells play a critical role in acute injury and graft failure. The aim of current study was to test NK cell infiltration and activation within allograft and the consequence of high DSA titers on graft outcomes in the absence of NK cell inactivation. C57BL/6 and B6.CCR5^-/- mice transplanted with complete MHC mismatched A/J or semi allogeneic (A/J x B6)F1 kidney grafts responded with equivalent DSA titers that reached peak by day 14 post-transplant and were maintained thereafter. 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. NK cell infiltration into A/J allografts was composed of distinct CD49b⁺ cell populations expressing low and high levels of NK1.1 that were first detected on day 7 post-transplant at numbers equivalent to those observed in (A/J x B6)F1 grafts. NK cell numbers of both populations continued to increase with time post-transplant within A/J allografts but decreased to background/isograft levels in (A/J x B6)F1 grafts. On day 7 post-transplant NK1.1^high cells were the predominant proliferating NK cells in A/J allografts, but NK1.1^low cells became the dominant proliferating NK cells on day 14. Histopathology of functioning (A/J x B6)F1 grafts at day 65 post-transplant indicated severe chronic injury with severe interstitial fibrosis, glomerulopathy and arteriopathy. Expression of genes encoding profibrogenic factors, including MMP7, connective tissue growth factor (CTGF), P-selectin, E-cadherin, and N-cadherin in A/J allografts continued to increase until the time of rejection. These increases were also observed with time post-transplant in (A/J x B6)F1 grafts with the exception of MMP7. These results indicate that NK cells synergize with DSA to cause acute kidney allograft injury and graft failure. Moreover, in the absence of NK cell activation within (A/J x B6)F1 grafts, the high titers of DSA cannot cause acute antibody-mediated rejection but induce the indolent development of interstitial fibrosis and glomerular injury that will eventually lead to graft dysfunction and failure at later times after transplantation.

CITATION INFORMATION: Yagisawa T., Dvorina N., Valujskikh A., Baldwin 3rd W., Fairchild R. Donor-Specific Antibody Mediates Chronic, but Not Acute, Kidney Allograft Rejection in the Absence of Natural Killer Cells Am J Transplant. 2017;17 (suppl 3).

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