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Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients
Marc Martínez-Llordella, … , Antoni Rimola, Alberto Sánchez-Fueyo
Marc Martínez-Llordella, … , Antoni Rimola, Alberto Sánchez-Fueyo
Published July 24, 2008
Citation Information: J Clin Invest. 2008;118(8):2845-2857. https://doi.org/10.1172/JCI35342.
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Research Article

Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients

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Abstract

A fraction of liver transplant recipients are able to discontinue all immunosuppressive therapies without rejecting their grafts and are said to be operationally tolerant to the transplant. However, accurate identification of these recipients remains a challenge. To design a clinically applicable molecular test of operational tolerance in liver transplantation, we studied transcriptional patterns in the peripheral blood of 80 liver transplant recipients and 16 nontransplanted healthy individuals by employing oligonucleotide microarrays and quantitative real-time PCR. This resulted in the discovery and validation of several gene signatures comprising a modest number of genes capable of identifying tolerant and nontolerant recipients with high accuracy. Multiple peripheral blood lymphocyte subsets contributed to the tolerance-associated transcriptional patterns, although NK and γδTCR+ T cells exerted the predominant influence. These data suggest that transcriptional profiling of peripheral blood can be employed to identify liver transplant recipients who can discontinue immunosuppressive therapy and that innate immune cells are likely to play a major role in the maintenance of operational tolerance in liver transplantation.

Authors

Marc Martínez-Llordella, Juan José Lozano, Isabel Puig-Pey, Giuseppe Orlando, Giuseppe Tisone, Jan Lerut, Carlos Benítez, Jose Antonio Pons, Pascual Parrilla, Pablo Ramírez, Miquel Bruguera, Antoni Rimola, Alberto Sánchez-Fueyo

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Figure 1

Study outline.

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Study outline.
Peripheral blood samples were obtained from a total of 80...
Peripheral blood samples were obtained from a total of 80 liver transplant recipients and 16 healthy individuals. Samples from TOL and non-TOL recipients were separated into a training set (38 samples) and a test set (23 samples). Differential microarray gene expression between TOL and non-TOL samples in the training set was first estimated employing SAM. This was followed by a search to identify genetic classifiers for prediction employing PAM, which resulted in a 26-probe signature. The PAM-derived signature was then employed to estimate the prevalence of tolerance among a cohort of 19 STA recipients. Next, among the genes identified by SAM and PAM, 68 genes were selected for validation on a qPCR platform, and the 34 validated targets were employed to identify additional classifiers employing MiPP. The 3 signatures identified by MiPP on the qPCR data set were then used to classify samples in the independent test of 11 TOL and 12 non-TOL recipients. None of the samples from the test set were employed for the genetic classifier discovery process.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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