A Need for Biomarkers of Operational Tolerance in Liver and Kidney Transplantation

Both kidney and particularly liver recipients can oc-casionally discontinue all immunosuppressive drugswithout undergoing rejection. These patients, whomaintain stable graft function off immunosuppres-sive drugs without clinically significant detrimentalimmune responses and/or immune deficits, are con-ventionally termed operationally tolerant and offer aunique paradigm of tolerance in humans. The immunecharacterizationofoperationallytoleranttransplantre-cipients has recently received substantial attention.Operationally tolerant patients might exhibit a signa-ture of tolerance that could potentially be useful toselect recipients amenable to drug minimization orwithdrawal. Furthermore, elucidation of the molecu-larpathwaysassociatedwiththeoperationaltolerancephenotypecouldprovidenoveltargetsfortherapy.Par-ticular emphasis has been placed on the use of bloodsamples and high-throughput transcriptional profilingtechniques. In liver transplantation, natural killer re-lated transcripts seem to be the most robust markersof operational tolerance, whereas enrichment in B cell-relatedgeneexpressionmarkershasbeenconsistentlyfoundinbloodsamplesfromoperationallytolerantkid-ney recipients, suggesting that different mechanismsoperate in the two situations. In this minireview, wesummarize the main achievements of recently pub-lished reports focused on the identification of tran-scriptional markers of operational tolerance, we high-light their mechanistic and clinical implications anddescribe their methodological limitations.Key words: Kidney, liver allograft,tolerance, transcrip-tome, transplantAbbreviations: AKT, v-akt murine thymoma viraloncogene homolog 1; BANK1, B-cell scaffold proteinwithankyrinrepeats1;FcR,ReceptortoFcfragmentofIgG; HC, healthy controls; IL10, interleukin 10; ITN, Im-muneToleranceNetwork;mRNA,messengerRNA;NK,natural killer; PBMC, peripheral blood mononuclearcell; qPCR, quantitative real-time PCR, TGF