Introduction. Development of tolerance biomarkers is important for interrogating the in-vivo immune status of patients entered in clinical trials of tolerance.

Methods. To determine the feasibility of developing mechanistically informative biomarkers of tolerance, we performed urinary cell mRNA profiling of 225-biopsy matched urine specimens from 170 kidney allograft recipients entered either in a Tolerance Trial, 19 samples from 10 recipients of HLA-mismatched living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx group), or enrolled in the Clinical Trials of Transplantation-04 and treated with conventional immunosuppressive (IS) drugs, 206 samples from 160 recipients. We measured absolute levels of 14 mRNAs encoding immunoregulatory proteins.

Results. Table 1 shows that levels of CTLA-4 mRNA are uniquely higher in the FCRx group compared to the ACR group (P<0.0001) and the No Rejection group (P<0.0001). FCRx Subgroup Analysis. Among the 10 FCRx subjects, 7 had stable donor chimerism (SDC), and were successfully withdrawn from all IS drugs; the remaining 3 had no or transient donor chimerism (TDC), diagnosed with subclinical ACR, and were on IS drugs. Urinary cell levels of granzyme B mRNA (P=0.02) and perforin mRNA (P=0.05) were lower in SDC vs. TDC (Fig.1A); very importantly the ratio of CTLA4 mRNA to perforin mRNA + granzyme B mRNA were higher in SDC vs. TDC (P=0.02, Fig. 1B). Conclusions. Our investigation, in addition to discovering a biomarker of allograft tolerance, demonstrates in clinically tolerant kidney graft recipients the dominance of negative regulation (CTLA-4) over cytotoxic effectors (perforin and granzyme B).

CITATION INFORMATION: Lee J, Leventhal J, Li C, Katapodis A, Ildstad S, Suthanthiran M. A Molecular Signature Characterized by Dominance of Negative Regulation over Cytotoxic Effectors in Tolerant Kidney Allograft Recipients. Am J Transplant. 2017;17 (suppl 3).

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