Phosphorylated S6 Ribosomal Protein: A Novel Biomarker of Antibody‐Mediated Rejection in Heart Allografts

• Published in: American journal of transplantation Vol. 6; no. 7; pp. 1560 - 1571
• Main Authors: Lepin, E. J., Zhang, Q., Zhang, X., Jindra, P. T., Hong, L. S., Ayele, P., Peralta, M. V. P., Gjertson, D. W., Kobashigawa, J. A., Wallace, W. D., Fishbein, M. C., Reed, E. F.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-07-2006
• Subjects: Acute Disease; Alloantibodies; Antibodies - immunology; Biomarkers; Biopsy; Cells, Cultured; endothelial cells; Endothelial Cells - immunology; Endothelial Cells - metabolism; Graft Rejection - enzymology; Graft Rejection - immunology; Heart Transplantation - immunology; heart/lung transplantation; histocompatibility antigens; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class II - immunology; Humans; Myocardium - metabolism; Phosphorylation; Protein Kinases - metabolism; rejection; Ribosomal Protein S6 - metabolism; Signal Transduction; Transplantation, Homologous - immunology
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01355.x

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.
Human anti‐HLA antibodies stimulate phosphorylation of S6 ribosomal protein in cultured endothelial cells, and increased phosphorylation of this protein is also seen in endomyocardial biopsies of heart transplants with antibody‐mediated rejection.