While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. We have previously reported that rejection of kidney allografts in CCR5^-/- mice is dependent on production of donor-specific antibody (DSA) and that NK cells play a critical role in acute injury and graft failure. The goal of the current study was to test the role of NK cell activation within allografts during antibody-mediated kidney allograft rejection in CCR5^-/- recipients. Wild type C57BL/6 and B6.CCR5^-/- mice were transplanted with complete MHC mismatched A/J or semi allogeneic (A/J x B6)F1 kidney grafts. B6.CCR5^-/- recipients rejected A/J kidney allografts between days 15-30 whereas wild type B6 and (A/J x B6)F1 allografts survived past day 70 post-transplant. On day 14 post-transplant DSA titers in response to A/J and (A/J x B6)F1 kidney allografts were equivalent and were maintained through day 60 in (A/J x B6)F1 recipients. On day 7 post-transplant, genes encoding cytolytic function in (A/J x B6)F1 allografts were highly expressed in B6.CCR5^-/- but not in B6.CCR5^-/-CD8^-/- recipients. From day 7 to 14 post-transplant NK cell numbers and NK cells expressing CD107a increased in A/J kidney allografts but not in (A/J x B6)F1 allografts. However, histologic examination of (A/J x B6)F1 allografts at day 60 post-transplant indicated the presence of chronic injury with severe interstitial fibrosis and glomerulopathy. This chronic injury was accompanied by marked increases in the expression of genes associated with tissue fibrogenesis, including connective tissue growth factor (CTGF), VCAM-1, E- and N-cadherin (CDH1 and CDH2) and MMP7 when compared to isografts on day 60 post-transplant. These results indicate that NK cells are activated to synergize with DSA to cause acute injury and rejection of complete allogeneic kidney allografts, and that in the absence of NK cell activation to semi-allogeneic F1 grafts DSA cannot cause acute kidney graft injury but induces the slow development of chronic glomerular injury.

CITATION INFORMATION: Yagisawa T, Tanaka T, Dvorina N, Valujskikh A, Baldwin 3rd W, Fairchild R. The Degree of NK Cell Activation Determines the Ability of Donor-Specific Antibodies to Mediate Acute vs. Chronic Rejection of Kidney Allografts. Am J Transplant. 2017;17 (suppl 3).

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