Presented at:
American Transplant Congress, Washington, DC,
June 3, 2003
Am J Transpl 3 Suppl 5:163, 2003
mRNA profiles of urinary cells distinguish allograft infiltrates associated with acute rejection from infiltrates that do not cause proximate acute rejection
Darshana Dadhania, Thangamani Muthukuma, Priya Anantharaman, Ruchuang Ding, Surya Seshan, Baogui Li, Meredith Aull, Choli Hartono, David Serur, Sandip Kapur, Manikkam Suthanthiran
Division of Nephrology and Transplantation Medicine,Dept. of Medicine, Weill Cornell Medical Center, New York Presbyterian Hospital, NY, NY; Dept. of Pathology, Weill Cornell Medical Center, New York Presbyterian Hospital, NY, NY; Dept. of Pharmacy, Weill Cornell Medical Center, New York Presbyterian Hospital, NY, NY; Dept. of Surgery, Weill Cornell Medical Center, New York Presbyterian Hospital, NY, NY
Acute cellular rejection(AR) is defined by presence of inflammatory infiltrates occupying >25% of allograft parenchyma & associated moderate tubulitis. It is unclear if interstitial infiltrates with mild tubulitis seen in the absence of AR & allograft dysfunction represents a benign process or an immunologically active process. We have correlated the presence of AR with elevated mRNA levels encoding granzyme B(GB), proteinase inhibitor9(PI9) and the integrin molecule CD103 in urinary cells. Herein we investigated molecular profiles of urinary cells obtained from patients with infiltrates w/o tubulitis(INF), patients with normal histology(NH) & patients with borderline changes(BL) and compared them to patients with AR. Our profile studies included GB, PI9, CD103, and chemokines CXCR3& IP10 given their importance in trafficking of cells into the allograft. One ug of total RNA was isolated from urinary cells & reverse transcribed to cDNA. Gene copies were measured using real-time quantitative PCR & expressed as mean +/- SE copies/ug of total RNA.
| NH N=9 | INF N=10 | BL N=6 | AR N=31 | NHvsAR & INFvsAR* | BLvsAR* | NHvsINF & NHvsBL & INFvsBL* | |
| GB | 14527 +/- 13500 | 4367 +/-1940 | 22152 +/- 9596 | 395599 +/-173924 | <.001 | <.05 | >.05 |
| PI9 | 5321 +/-2192 | 4890 +/-1720 | 41490 +/-23433 | 647807 +/-399256 | <.001 | >.05 | >.05 |
| CXCR3 | 3643 +/-1034 | 3424 +/-899 | 28667 +/-11929 | 277276 +/-119789 | <.001 | >.05 | >.05 |
| IP10 | 2862 +/-1710 | 6317 +/-3685 | 11610 +/-9301 | 420146 +/-154579 | <.001 | <.05 | >.05 |
| CD103 | 111 +/-99 | 306 +/-167 | 967 +/-529 | 8968 +/-2824 | <.001 | <.05 | >.05 |
Our data demonstrates that infiltrates that do not cause AR are molecularly quiescent and mRNA profile of INF resembles the profile of those with NH. BL biopsies express lower levels of IP10, GB and CD103 as compared to AR. IP10 is important for recruitment of TH1type Tcells & CD103 is critical for intraepithelial localization of CD8+CTL while GB is an important cytotoxic Tcell effector molecule. Thus, BL changes may not progress to AR& may not merit AR therapy. Our mRNA profiling studies provide a molecular basis for the differential clinical outcome of cellular traffic into the allograft and resolve the controversy regarding the significance of borderline acute rejection.