Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts

Transplantation. 2010 Dec 27;90(12):1381-7. doi: 10.1097/TP.0b013e3181ffbadd.

Abstract

Background: The positive costimulatory proteins OX40 and OX40L and negative regulatory proteins programmed death (PD)-1, PD ligand 1, and PD ligand 2 have emerged as significant regulators of acute rejection in experimental transplantation models.

Methods: We obtained 21 urine specimens from 21 renal allograft recipients with graft dysfunction and biopsy-confirmed acute rejection and 25 specimens from 25 recipients with stable graft function and normal biopsy results (stable). Urinary cell levels of mRNAs were measured using real-time quantitative polymerase chain reaction assays, and the levels were correlated with allograft status and outcomes.

Results: Levels of OX40 mRNA (P<0.0001, Mann-Whitney test), OX40L mRNA (P=0.0004), and PD-1 mRNA (P=0.004), but not the mRNA levels of PD ligand 1 (P=0.08) or PD ligand 2 (P=0.20), were significantly higher in the urinary cells from the acute rejection group than the stable group. Receiver operating characteristic curve analysis demonstrated that acute rejection is predicted with a sensitivity of 95% and a specificity of 92% (area under the curve=0.98, 95% confidence interval 0.96-1.0, P<0.0001) using a combination of levels of mRNA for OX40, OX40L, PD-1, and levels of mRNA for the previously identified biomarker Foxp3. Within the acute rejection group, levels of mRNA for OX40 (P=0.0002), OX40L (P=0.0004), and Foxp3 (P=0.04) predicted acute rejection reversal, whereas only OX40 mRNA levels (P=0.04) predicted graft loss after acute rejection.

Conclusion: A linear combination of urinary cell levels of mRNA for OX40, OX40L, PD-1, and Foxp3 was a strong predictor of acute rejection in human renal allograft biopsies. This prediction model should be validated using an independent cohort of renal allograft recipients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adult
  • Antigens, CD / genetics*
  • Antigens, CD / urine
  • Antigens, Differentiation / genetics*
  • Antigens, Differentiation / urine
  • B7-H1 Antigen
  • Continental Population Groups
  • Creatinine / blood
  • Female
  • Graft Rejection / genetics
  • Graft Rejection / urine*
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Intercellular Signaling Peptides and Proteins / urine
  • Kidney Transplantation / physiology*
  • Male
  • Middle Aged
  • OX40 Ligand / genetics*
  • OX40 Ligand / urine
  • Predictive Value of Tests
  • Programmed Cell Death 1 Ligand 2 Protein
  • RNA, Messenger / urine
  • ROC Curve
  • Transplantation, Homologous

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • B7-H1 Antigen
  • CD274 protein, human
  • Intercellular Signaling Peptides and Proteins
  • OX40 Ligand
  • OX40Ig
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • RNA, Messenger
  • Creatinine