2. Innate type immune cells appear to be involved in the maintenance of the tolerant state in human liver recipients.
3. Transcriptional profiles from tolerant liver and kidney recipients show minimal overlap.
A fraction of liver transplant recipients can discontinue all immunosuppressive therapies without undergoing rejection (operational tolerance). However, accurate identification of these recipients remains a challenge. We have employed both Affymetrix microarrays and real-time PCR technologies to explore in peripheral blood samples the differential gene expression between tolerant recipients and those requiring indefinite immunosuppressive therapy, and ultimately to design a clinically applicable molecular test of tolerance in liver transplantation. To do so we have studied peripheral blood transcriptional patterns from 80 liver transplant recipients in whom a previous attempt at immunosuppression withdrawal had been attempted, and from 96 recipients enrolled in a prospective trial of immunosuppression withdrawal. This has resulted in the discovery and validation of several gene signatures comprising a modest number of genes capable of identifying tolerant and non-tolerant recipients with high accuracy. Multiple peripheral blood lymphocyte subsets and functional pathways contribute to the tolerance-associated transcriptional patterns, but NK-related genes appear to exert a predominant influence. These patterns substantially differ from the expression profile identified in tolerant kidney recipients. We conclude 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 operationally tolerance in liver transplantation.
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