GSE210164
Transcriptome analysis of graft liver provides insight into the immune response of rat liver transplantation
Background: As an “immune-privileged organ”, the rate of spontaneous and operational tolerance was higher after liver transplantation (LT) compared with other solid organs. However, modern immunosuppression regimens still have multiple complications, which require a deeper understanding of the real mechanism of inducing immune tolerance. Methods: Homogenic and allogeneic rat LT models were established, and recipient tissue was collected on postoperative day 7. The degree of LT rejection was evaluated by liver pathological changes and liver function. Differentially expressed genes (DEGs) were detected by transcriptome sequencing and identified by RT-PCR. The functional properties of DEGs were characterized by the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway analyses. The cells infiltrating the graft and recipient spleen and peripheral blood were evaluated by immunofluorescence assays and flow cytometry. Result: A total of 1465 DEGs were screened, including 1177 up-regulated genes and 288 down-regulated genes. GO enrichment and KEGG pathway analysis indicated that DEGs were involved in several immunobiological processes, including immune system process, immune response, regulation of immune response, T cell activation, cytokine-cytokine receptor interaction, allograft rejection, Th1,Th2 and Th17 cell differentiation. Reactome results showed that PD-1 signaling was also enriched. Further research confirmed that the expression of multiple immune cell markers increased, and most marker of T cell exhaustion changed significantly. Flow cytometry results showed that the proportion of Treg decreased in the allogeneic group, while CD4+PD-1+ T and CD8+PD-1+ T cells increased. Conclusion: This study, to our knowledge, was the first to reveal the impact of liver transplantation rejection on the liver at the omics level. Our results revealed that the progression of LT rejection involves multiple immune cells, activation of various immune pathways and special changes of immune checkpoints, which provides potential reference for potential risk assessment and pathogenesis. However, further clinical validation is also needed. Overall design: Lewis and Brown Norway (BN) rats were utilized as liver donors and recipients to establish allogeneic rejection models.   Lewis-rats were used to construct homogenic tolerance models. mRNA was isolated from graft  (three samples per group) and analyzed using RNA-seq.