Article

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

UCLA Immunogenetics Center, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
American Journal of Transplantation (Impact Factor: 6.19). 08/2006; 6(7):1560-71. DOI: 10.1111/j.1600-6143.2006.01355.x
Source: PubMed

ABSTRACT 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.

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    • "Interestingly, the majority of studies investigating antibody activity in EC injury were mediated by HLA class I monoclonal antibodies leaving clear need to investigate class II antibodies. One study investigated the effects of class I and II antibodies on EC on cardiac allografts and showed that phosphorylation of S6 ribosomal protein (S6RP), a downstream target of the PI3K/Akt/mTOR pathway, was a biomarker of antibody mediated rejection [67]. The authors demonstrated that ligation of HLA class I and class II molecules on EC resulted in increased phosphorylation of S6RP. "
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    • "Macrophages are now recognized as a common intracapillary cell in AMR in kidney (Tinckam et al., 2005) and heart (Lepin et al., 2006) allografts. Typically, the PTC are dilated. "
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