Introduction: Although the liver is less immunogenic than other solid organs, most liver transplant recipients receive lifelong immunosuppression. Total lymphoid irradiation (TLI) is part of a protocol that is currently being used in the clinic to induce tolerance to renal allografts. Our goal was to identify the miRNAs of tolerant graft recipients.in an experimental model of TLI-induced tolerance. Methods: To identify the miRNAs associated with TLI-induced tolerance we examined syngeneic (syn) recipients (DA into DA) and allogeneic (allo) recipients (DA into Lewis) of OLT that received post-transplant TLI, allo-recipients (DA into Lewis) that were not treated post-transplant, and normal DA rats. Untreated allo-recipients reject their grafts within 10 days whereas TLI treated recipients have long-term graft survival (>100 days) thus miRNAs were examined at two time points, seven days (d7) post-transplant (allo-untreated, allo-TLI, syn-TLI and at 100 days (d100) post-transplant (allo-TLI), using Taqman array cards. Results: Through unsupervised hierarchical clustering, two main groups emerged, allo-livers obtained on d7 irrespective of TLI treatment and syn-livers clustered with allo-TLI d100 livers. Similarly, principal component analysis demonstrated the tolerant allo-TLI livers (d100) were closely related to the syn-liver grafts. In addition, several miRNAs, including miR142-3p, miR142-5p, miR147, miR181a, miR184 and miR342-3p, demonstrated increased expression in tolerant livers (both at d7 and d100) as compared to syngeneic grafts, however these miRNAs are also increased during acute rejection. Two miRNAs, miR196b and miR499 are specifically increased in allografts with established tolerance (d100). Validation of these miRNAs and determination of target mRNAs are on-going. Conclusions: Our results suggest the miRNA profile of tolerant allografts is very similar to the profile observed in syngeneic grafts. There are however a few miRNAs that may be attractive biomarkers of TLI-induced tolerance and allograft stability

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