A three-gene assay for monitoring immune quiescence in kidney transplantation

Silke Roedder, Li Li, Michael N. Alonso, Szu Chuan Hsieh, Minh Thien Vu, Hong Dai, Tara K. Sigdel, Ian Bostock, Camila Macedo, Diana Metes, Adrianna Zeevi, Ron Shapiro, Oscar Salvatierra, John Scandling, Josefina Alberu, Edgar Engleman, Minnie M. Sarwal

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

Organ transplant recipients face life-long immunosuppression and consequently are at high risk of comorbidities. Occasionally, kidney transplant recipients develop a state of targeted immune quiescence (operational tolerance) against an HLA-mismatched graft, allowing them to withdraw all immunosuppression and retain stable graft function while resuming immune responses to third-party antigens. Methods to better understand and monitor this state of alloimmune quiescence by transcriptional profiling may reveal a gene signature that identifies patients for whom immunosuppression could be titrated to reduce patient and graft morbidities. Therefore,we investigated 571 unique peripheral blood samples from348HLA-mismatched renal transplant recipients and 101 nontransplant controls in a four-stage study including microarray, quantitative PCR, and flow cytometry analyses. We report a refined and highly validated (area under the curve, 0.95; 95% confidence interval, 0.92 to 0.97) peripheral blood three-gene assay (KLF6, BNC2, CYP1B1) to detect the state of operational tolerance by quantitative PCR. The frequency of predicted alloimmune quiescence in stable renal transplant patients receiving long-term immunosuppression (n=150) was 7.3% by the three-gene assay. Targeted cell sorting of peripheral blood fromoperationally tolerant patients showed a significant shift in the ratio of circulating monocyte-derived dendritic cells with significantly different expression of the genes constituting the three-gene assay. Our results suggest that incorporation of patient screening by specific cellular and gene expression assays may support the safety of drug minimization trials and protocols.

Original languageEnglish
Pages (from-to)2042-2053
Number of pages12
JournalJournal of the American Society of Nephrology : JASN
Volume26
Issue number8
DOIs
StatePublished - 1 Aug 2015

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