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BACKGROUND AND AIMS TOMOGRAM, a European multicenter study, recently identified a new cohort of kidney transplant recipients (KTR) with operational tolerance (OT) with the aim to identify new transcriptomic signatures of OT. METHOD RNA sequencing of peripheral blood was evaluated in 15 OT KTR identified by TOMOGRAM, 23 stable KTR (≥15 years, STA), 14 KTR with transplant glomerulopathy (≥1 year, CR), 14 CyA-treated primary GN patients and 14 healthy controls (HC). The ability to discriminate OT from others was analyzed using three classifiers (GLMNET, voomNSC and SVM-RFE) with 10-fold cross-validation and visualized by principal component analysis (PCA) of molecular archetypes. RESULTS Peripheral blood transcriptome of OT patients is similar to the STA group (AUC 0.8). Also, in PCA of molecular archetypes, direction of correlation suggested similarity between STA and OT and their anti-correlation to CR (Figure 1). Top 10 transcripts differentiated OT from CR were assessed in prospective independent cohort (n = 396) to predict premature graft loss. Multivariable Cox regression model based on the expression of 5 of those transcripts at 3 time-points was associated with graft loss at 3 years with an AUC = 0.815. CONCLUSION Identification of the OT peripheral molecular signature among stable KTR is not feasible. Instead, novel peripheral molecular markers associated with premature graft loss were identified.

BACKGROUND Regulatory T cells have been suggested to down-regulate the alloimmune response. The aim of this prospective open study was to evaluate the effects of different inductive agents on peripheral blood regulatory T cells in kidney transplant patients and to analyse their association with short-term graft outcome. METHODS Regulatory and effector T cell numbers in peripheral blood were determined by flow cytometry in 71 prospectively followed kidney transplant recipients at postoperative day 0, 7, 14, 21, 28, 60 and 90. Patients were treated with a calcineurin inhibitor-based triple immunosuppression with polyclonal rabbit anti-thymocyte globulin (rATG, n = 28), basiliximab, the anti-CD25 monoclonal antibody (n = 18) or without induction (controls, n = 25). Flow cytometry data were correlated to rejection incidence. RESULTS Compared to controls, CD4(+)CD25(+)FoxP3(+) regulatory T-cell expansion among CD4(+) T cells was noticed in the rATG group at all post-transplant time-points by Day 14 (P < 0.001). A significant decrease in Treg frequency (P < 0.001) and concurrently a transient increase of CD4(+)CD25(low/-)FoxP3(+) population were observed in basiliximab-treated patients 7-60 days post-transplantation. Biopsy-proven acute rejection occurred in 16.7% of controls, 10.7% of the rATG group and in 11.1% of the basiliximab group. Higher CD4(+)FoxP3(+)/CD8(+)CD45RA(+)CD62L(-) ratios were observed repeatedly in those patients after basiliximab induction who were rejection free (P < 0.01). CONCLUSIONS In this study, the rATG induction therapy was associated with an expansion of regulatory cells. Sustained high CD4(+)FoxP3(+)/Teff ratios were associated with the absence of rejection after basiliximab induction.