The maintenance of stable allograft status in the absence of immunosuppression, known as operational tolerance, can be achieved in a small proportion of liver transplant recipients, but we lack reliable tools to predict its spontaneous development. We conducted a prospective, multi-center, biomarker-strategy design, immunosuppression withdrawal clinical trial to determine the utility of a predictive biomarker of operational tolerance. The biomarker test, originally identified in a patient cohort with high operational tolerance prevalence, consisted of a 5-gene transcriptional signature measured in liver tissue collected before initiating immunosuppression weaning. 116 adult stable liver transplant recipients were randomized 1:1 to either Arm A (immunosuppression withdrawal regardless of biomarker status) or Arm B (immunosuppression withdrawal in biomarker-positive recipients). Immunosuppression withdrawal was initiated in 82 participants, rejection occurred in 54 (67.5%), successful discontinuation of immunosuppression was achieved in 22 (27.5%), but only 13 (16.3%) met operational tolerance histological criteria (10 in Arm A, 3 in Arm B). The biomarker test did not yield useful information in selecting patients able to successfully discontinue immunosuppression. Operational tolerance was associated with time post-transplantation, recipient age, presence of circulating exhausted CD8+ T cells, and a reduced number of immune synapses within the graft. TRIAL REGISTRATION: ISRCTN 47808000 and EudraCT 2014-004557-14.
Keywords: DSA; LT; biomarker; gene-expression profiling; immunosuppression minimization; tolerance.
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