TY - JOUR
T1 - Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts
AU - Kohei, Naoki
AU - Tanaka, Toshiaki
AU - Tanabe, Kazunari
AU - Masumori, Naoya
AU - Dvorina, Nina
AU - Valujskikh, Anna
AU - Baldwin, William M.
AU - Fairchild, Robert L.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - antibody-mediated rejection
KW - kidney allograft
KW - NK cells
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U2 - 10.1016/j.kint.2016.02.030
DO - 10.1016/j.kint.2016.02.030
M3 - Article
C2 - 27165816
AN - SCOPUS:84978101505
SN - 0085-2538
VL - 89
SP - 1293
EP - 1306
JO - Kidney International
JF - Kidney International
IS - 6
ER -