title: Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts.
abstract: While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) mice were transplanted with complete MHC-mismatched A/J kidney grafts, and intragraft inflammatory components were followed to rejection. B6.CCR5(-/-) and B6.CD8(-/-)/CCR5(-/-) recipients rejected kidney allografts by day 35, whereas 65% of allografts in wild-type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8(-/-)/CCR5(-/-) recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts.
authors.affiliation: Department of Immunology and the Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA; Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kohei
authors.affiliation: Department of Immunology and the Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA; Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tanabe
authors.affiliation: Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Masumori
authors.affiliation: Department of Immunology and the Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Dvorina
authors.affiliation: Department of Immunology and the Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Valujskikh
authors.affiliation: Department of Immunology and the Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Baldwin
authors.affiliation: Department of Immunology and the Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA. Electronic address: fairchr@ccf.org.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fairchild
mesh_terms: D064591:Allografts / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D016030:Kidney Transplantation / Q000009:adverse effects*; D007694:Killer Cells, Natural / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000235:genetics; D014019:Tissue Donors; D066027:Transplant Recipients; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D000906:Antibodies; C000592874:CCR5 protein, mouse; D019713:Receptors, CCR5
keywords: NK cells; antibody-mediated rejection; kidney allograft