TY - JOUR
T1 - In the absence of natural killer cell activation donor-specific antibody mediates chronic, but not acute, kidney allograft rejection
AU - Yagisawa, Takafumi
AU - Tanaka, Toshiaki
AU - Miyairi, Satoshi
AU - Tanabe, Kazunari
AU - Dvorina, Nina
AU - Yokoyama, Wayne M.
AU - Valujskikh, Anna
AU - Baldwin, William M.
AU - Fairchild, Robert L.
N1 - Publisher Copyright:
© 2018 International Society of Nephrology
PY - 2019/2
Y1 - 2019/2
N2 - Antibody mediated rejection (ABMR) is a major barrier to long-term kidney graft survival. Dysregulated donor-specific antibody (DSA) responses are induced in CCR5-deficient mice transplanted with complete major histocompatibility complex (MHC)-mismatched kidney allografts, and natural killer (NK) cells play a critical role in graft injury and rejection. We investigated the consequence of high DSA titers on kidney graft outcomes in the presence or absence of NK cell activation within the graft. Equivalent serum DSA titers were induced in CCR5-deficient B6 recipients of complete MHC mismatched A/J allografts and semi-allogeneic (A/J x B6) F1 kidney grafts, peaking by day 14 post-transplant. A/J allografts were rejected between days 16-28, whereas B6 isografts and semi-allogeneic grafts survived past day 65. On day 7 post-transplant, NK cell infiltration into A/J allografts was composed of distinct populations expressing high and low levels of the surface antigen NK1.1, with NK1.1low cells reflecting the highest level of activation. These NK cell populations increased with time post-transplant. In contrast, NK cell infiltration into semi-allogeneic grafts on day 7 was composed entirely of NK1.1high cells that decreased thereafter. On day 65 post-transplant the semi-allogeneic grafts had severe interstitial fibrosis, glomerulopathy, and arteriopathy, accompanied by expression of pro-fibrogenic genes. These results suggest that NK cells synergize with DSA to cause acute kidney allograft rejection, whereas high DSA titers in the absence of NK cell activation cannot provoke acute ABMR but instead induce the indolent development of interstitial fibrosis and glomerular injury that leads to late graft failure.
AB - Antibody mediated rejection (ABMR) is a major barrier to long-term kidney graft survival. Dysregulated donor-specific antibody (DSA) responses are induced in CCR5-deficient mice transplanted with complete major histocompatibility complex (MHC)-mismatched kidney allografts, and natural killer (NK) cells play a critical role in graft injury and rejection. We investigated the consequence of high DSA titers on kidney graft outcomes in the presence or absence of NK cell activation within the graft. Equivalent serum DSA titers were induced in CCR5-deficient B6 recipients of complete MHC mismatched A/J allografts and semi-allogeneic (A/J x B6) F1 kidney grafts, peaking by day 14 post-transplant. A/J allografts were rejected between days 16-28, whereas B6 isografts and semi-allogeneic grafts survived past day 65. On day 7 post-transplant, NK cell infiltration into A/J allografts was composed of distinct populations expressing high and low levels of the surface antigen NK1.1, with NK1.1low cells reflecting the highest level of activation. These NK cell populations increased with time post-transplant. In contrast, NK cell infiltration into semi-allogeneic grafts on day 7 was composed entirely of NK1.1high cells that decreased thereafter. On day 65 post-transplant the semi-allogeneic grafts had severe interstitial fibrosis, glomerulopathy, and arteriopathy, accompanied by expression of pro-fibrogenic genes. These results suggest that NK cells synergize with DSA to cause acute kidney allograft rejection, whereas high DSA titers in the absence of NK cell activation cannot provoke acute ABMR but instead induce the indolent development of interstitial fibrosis and glomerular injury that leads to late graft failure.
KW - NK cells
KW - antibody-mediated rejection
KW - kidney allograft
UR - http://www.scopus.com/inward/record.url?scp=85057395028&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85057395028&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2018.08.041
DO - 10.1016/j.kint.2018.08.041
M3 - Article
C2 - 30503624
AN - SCOPUS:85057395028
SN - 0085-2538
VL - 95
SP - 350
EP - 362
JO - Kidney international
JF - Kidney international
IS - 2
ER -