Current success in liver transplantation (LTX) relies on life-time administration of non-specific immunosuppressive drugs, leaving patients prone to infection and cancer. Previous reports indicated about 25% patients after LTX can be completely weaned from immunosuppression. However, the susceptibility genes and specific molecular mechanisms that underlay tolerance remain unidentified. The goal of this project is to identify the genetic biomarkers associated with LTX tolerance. We established a mouse model in which LTX donors and recipients are CD-1 outbred mice, where ~30% LTX achieved long-term survival. Next, we carried out mRNA microarray expression profiling in both tolerance and acute rejection groups. The tolerance group was divided into three subgroups: Day 0, Day 10 and Day 70; the acute rejection group was divided into two subgroups: Day 0 and Day 10. There were 3 samples in each subgroup. High quality mRNA preparations were extracted from individual mouse blood samples. We selected Mouse Transcriptome Assay 1.0 for mRNA microarray, which includes 23,000 genes and 332,000 exons, and the Affymetrix Expression Console 1.4 software was used for data analysis.

Table shows the candidate gene level of differential mRNA expression analysis using a microarray cut-off fold change >10 and P-value <1[times]10^-3 between tolerance and rejection groups on day 0, 10 and 70. The peak-fold change of 248.58 (up-regulation) and -1418.86 (down-regulation) was observed; and the lowest ANOVA P-value was <6.5[times]10^-5 (up-regulation) and <3[times]10^-6 (down-regulation). Figure shows two main different patterns of gene expression with significant differences between the tolerance day 10 and acute rejection day 10 after LTX. Through these studies, we continue to identify novel diagnostic biomarkers that are associated with LTX tolerance, which can be correlated with key cellular pathways that have been demonstrated in tolerant LTX recipients. The data obtained in animal studies may provide valuable information as a starting point for human studies.

CITATION INFORMATION: Shen G.-Q, Morita M, Miller C, Hashimoto K, Lu L, Qian S, Fung J. Identification of Novel Diagnostic Biomarkers in Liver Transplantation Tolerance. Am J Transplant. 2017;17 (suppl 3).

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