A Common Peripheral Blood Gene Set for Diagnosis of Operational Tolerance in Pediatric and Adult Liver Transplantation

Abstract

To identify biomarkers of operational tolerance in pediatric and adult liver transplant recipients, transcriptional profiles were examined from 300 samples by microarrays and Q-PCR measurements of blood specimens from pediatric and adult liver transplant recipients and normal tissues. Tolerance-specific genes were validated in independent samples across two different transplant programs and validated by Q-PCR. A minimal set of 13 unique genes, highly expressed in natural killer cells (p = 0.03), were significantly expressed in both pediatric and adult liver tolerance, irrespective of different clinical and demographic confounders. The performance of this gene set by microarray in independent samples was 100% sensitivity and 83% specificity and the AUC was 0.988 for only three genes by Q-PCR. 26% of adults and 64% of children with excellent liver allograft function, on minimal or dual immunosuppression, showed high prediction scores for tolerance. Novel peripheral transcriptional profiles can be identified in operational tolerance in pediatric and adult recipients of liver allografts, suggesting a high incidence of a pro-tolerogenic phenotype in stable patients on chronic immunosuppression. Given the high incidence of viral infections and malignancies in liver transplant recipients, this gene set provides an important monitoring tool that can move the field toward personalized and predictive medicine in organ transplantation.

A Three-Gene Assay for Monitoring Immune Quiescence in Kidney Transplantation

“…7,8 These patients are conventionally called operationally tolerant (TOL) and provide a unique repertoire for study and development of monitoring methods that help to differentiate transplant recipients receiving immunosuppression with differing immune thresholds and thus help identify patients who may safely minimize their immunosuppression. Transcriptional studies in peripheral blood by our group and others have identified gene signatures for TOL after kidney [7][8][9] and liver 10,11 transplantation. But these studies are limited by insufficient cross-validations in independent cohorts, and, importantly, the frequency of a TOL signature is poorly defined in stable transplant recipients receiving immunosuppression.…”

Reply to “Cytomegalovirus-Induced γδ T Cells During Rejection: An Ambivalent T Cell”

“…These observations surprised us, because they suggest that primary CMV infection may be associated with development of immunological tolerance to liver allografts, contrasting to findings from previous animal studies. In trying to obtain further evidence for this unexpected finding, we measured peripheral Vd1/Vd2 gd T cells, because an increased peripheral Vd1/Vd2 gd T cells ratio is the only biomarker that is consistently associated with operational tolerance after LT in independent studies (3)(4)(5). Indeed, we observed increased Vd1/Vd2 ratios in CMV IgG Dþ/Rcompared to D-/R-and Rþ LT patients, supporting our conclusion that primary CMV infection may be associated with development of immunological tolerance to liver allografts.…”

Biomarkers of Immune Tolerance in Liver Transplantation

“…К настоящему времени опубликованы результа-ты ряда клинических исследований, посвященных сравнительному изучению транскрипции различ-ных генов в образцах крови реципиентов печени, у которых развилась или не развилась иммунная толерантность [6,39]. Одна из сложностей интер-претации данных таких исследований связана с использованием реципиентами группы без индук-ции толерантности иммуносупрессантов, которые могут оказывать влияние на получаемый резуль-тат.…”

“…Одно из самых больших исследований в транс-плантомике было проведено в нескольких центрах США и включало реципиентов печени взрослого и детского возраста, получавших трансплантат как от живого, так и от умершего донора [39]. В этом ис-следовании были идентифицированы 13 генов, экс-прессия которых отличалась у реципиентов с толе-рантностью, независимо от возраста и типа донора.…”

“…В последние 10-15 лет проводилось значитель-ное количество исследований, посвященных по-иску биомаркеров и методов для идентификации пациентов, которым можно безопасно минимизи-ровать или отменить иммуносупрессию [6,38,39]. Несмотря на то что к настоящему времени опубли-ковано большое количество работ с описанием но-вых биомаркеров и методик их определения [28,29,[43][44][45][46], большая часть биомаркеров не протестиро-вана в многоцетровых рандомизированных клини-ческих испытаниях.…”