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Urinary Cell Levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and Acute Rejection of Human Renal Allografts

Author(s): Afaneh, C (Afaneh, Cheguevara); Muthukumar, T (Muthukumar, Thangamani); Lubetzky, M (Lubetzky, Michelle); Ding, RC (Ding, Ruchuang); Snopkowski, C (Snopkowski, Catherine); Sharma, VK (Sharma, Vijay K.); Seshan, S (Seshan, Surya); Dadhania, D (Dadhania, Darshana); Schwartz, JE (Schwartz, Joseph E.); Suthanthiran, M (Suthanthiran, Manikkam) Source: TRANSPLANTATION, 90 (12): 1381-1387 DEC 27 2010

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. 

Author(s):  Afaneh, C (Afaneh, Cheguevara); Muthukumar, T (Muthukumar, Thangamani); Lubetzky, M (Lubetzky, Michelle); Ding, RC (Ding, Ruchuang); Snopkowski, C (Snopkowski, Catherine); Sharma, VK (Sharma, Vijay K.); Seshan, S (Seshan, Surya); Dadhania, D (Dadhania, Darshana); Schwartz, JE (Schwartz, Joseph E.); Suthanthiran, M (Suthanthiran, Manikkam) 
Source:  TRANSPLANTATION, 90 (12): 1381-1387 DEC 27 2010 
Language:  English 
Document Type:  Article 
Author Keywords:  Acute rejection; OX40; Costimulation; Urinary biomarkers 
KeyWords Plus:  RESPONSES IN-VIVO; COSTIMULATORY PATHWAYS; ALLOIMMUNE RESPONSES; TRANSPLANT RECIPIENTS; T-CELLS; TOLERANCE; ACCEPTANCE; SURVIVAL; BLOCKING; MEMORY 
Addresses:  : [Afaneh, Cheguevara] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Surg, New York, NY USA; [Muthukumar, Thangamani; Lubetzky, Michelle; Ding, Ruchuang; Snopkowski, Catherine; Sharma, Vijay K.; Dadhania, Darshana; Suthanthiran, Manikkam] New York Presbyterian Hosp, Weill Cornell Med Ctr, Div Nephrol & Hypertens, Dept Med, New York, NY USA; [Muthukumar, Thangamani; Dadhania, Darshana; Suthanthiran, Manikkam] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Transplantat Med, New York, NY USA; [Sharma, Vijay K.; Dadhania, Darshana] Rogosin Inst, New York, NY USA; [Seshan, Surya] New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Pathol, New York, NY USA; [Schwartz, Joseph E.] SUNY Stony Brook, Dept Psychiat, Stony Brook, NY 11794 USA 
Reprint Address:  Suthanthiran, M, New York Presbyterian Weill Cornell Med Ctr, Div Nephrol, Dept Transplantat Med, 525 E 68th St,Box 3, New York, NY 10065 USA. 
Funding Agency:  This work was supported in part by an award (R37 AI051652) from NIAID, NIH, and an award (NPRP 08-503-3-111) from the Qatar National Research Foundation (M. S.); by a grant ULI RR 024996 of the Clinical and Translational Science Center at Weill Cornell Medical College; by an award (T32 HL08382401) from NIH to Todd Evans (C. A.); and in part by the Empire Clinical Research Investigator Program (ECRIP) New York State Award (M.L.).
Publisher:  LIPPINCOTT WILLIAMS & WILKINS 
Publisher Address:  530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA 
ISSN:  0041-1337 
29-char Source Abbrev.:  TRANSPLANTATION 
ISO Source Abbrev.:  Transplantation 
Subject Category:  Immunology; Surgery; Transplantation 
DOI: 10.1097/TP.0b013e3181ffbadd
ISI Document Delivery No.:  695NG 
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