Phosphorylated S6 ribosomal protein: a novel biomarker of antibody-mediated rejection in heart allografts.
We tested the hypothesis that phosphorylation of S6 ribosomal protein (S6RP), a downstream target of the PI3K/Akt/mTOR pathway, is a biomarker of antibody-mediated rejection (AMR) in heart allografts. Primary cultures of human aortic and microvascular endothelial cells (EC) were treated with anti-HLA class I and class II antibodies (Ab) and cell lysates were studied for phosphorylation of S6 ribosmal protein at Serine235/236 (p-S6RP). Treatment of cultured EC with anti-class I and class II Ab stimulated S6RP phosphorylation. Immunohistochemical techniques were used to detect the level of p-S6RP in endomyocardial biopsies (n = 131) from 46 heart transplant recipients and the results were correlated with histopathological diagnosis of rejection, C4d staining, production of posttransplant anti-HLA Ab and clinical outcome. Increased phosphorylation of S6RP in endomyocardial biopsies was significantly associated with the diagnosis of AMR (p < 0.0001). No significant association between acute cellular rejection (ACR) and p-S6RP was observed. C4d staining was positively associated with both AMR and p-S6RP. Posttransplant anti-HLA class II Ab production was also significantly associated with a positive p-S6RP status in cardiac biopsies. These results indicate that p-S6RP is a useful biomarker for the diagnosis of AMR.
Lepin
E J
EJ
UCLA Immunogenetics Center, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Zhang
Q
Q
Zhang
X
X
Jindra
P T
PT
Hong
L S
LS
Ayele
P
P
Peralta
M V P
MV
Gjertson
D W
DW
Kobashigawa
J A
JA
Wallace
W D
WD
Fishbein
M C
MC
Reed
E F
EF
D000208:Acute Disease; D000906:Antibodies / Q000276:immunology*; D015415:Biomarkers; D001706:Biopsy; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000201:enzymology / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D015398:Signal Transduction; D014184:Transplantation, Homologous / Q000276:immunology
D000906:Antibodies; D015415:Biomarkers; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D038601:Ribosomal Protein S6; D011494:Protein Kinases