*Purpose: TOMOGRAM is a European multicenter study, that aims to identify transcriptomic and genomic signatures of operational tolerance (OT) in a recently identified cohort of OT kidney transplant recipients.

*Methods: RNA sequencing of peripheral blood was evaluated in 15 OT patients identified by the TOMOGRAM consortium, 23 stable patients (≥ 15 years on immunosuppression, STA), 14 CABMR patients (CR), and 14 healthy controls (HC). Differential expression was researched using DESEq2 and gene annotation analysis using Enrichr. Besides immunosuppression-unadjusted model, robust negative-binomial regression model was created to adjust for immunosuppression. The model was trained on homogeneous group of STA patients.

*Results: Using the model unadjusted for immunosuppression, no differences in transcriptomic profiles between OT, STA and HC groups were found. Nine transcripts were significantly upregulated and 2 downregulated in OT compared to CR group. The number of deregulated transcripts substantially increased when the model was adjusted for immunosuppression. Gene annotation analysis of top ranked deregulated 1109 transcripts (FC>2, adjusted p value <0.0001) showed deregulation of biological processes related to interferon-γ-mediated signaling (p=1.4*10^-5), response to cytokine (p=1.5*10^-5), type I interferon signaling (p=0.00036), regulation of NF-kappaB signaling (p=0.0021), cytokine-mediated signaling (p=0.019) and neutrophil mediated immunity (p=0.033). While interferon-γ-mediated and type I interferon signaling were related to transcripts increased in CR, neutrophils associated transcripts were increased in OT. Comparing OT and CR, cell transcripts showed enrichment of CD19 B cells (p=1.6*10^-9) in CR, while CD56NK cells (p=2.5*10^-11) and CD8 T cells (p=1.6*10^-11) transcripts in OT. To reveal probability of operational tolerance inside STA group, 13 transcripts able to discriminate OT and CR cohorts with high AUC (>0.89) were used in PCA analysis (ADGRG3, ATG2A, GDPD5, IL16, MX2, SLA2, PRKD2, SLIRP, GNLY, SRCAP, ARGHAP9, IGHM, CD5). The high probability of OT signature was found in a single STA patient.

*Conclusions: Contrary to previous reports which pointed out towards naïve B cell signatures, this first in class RNA sequencing unbiased study stresses that OT patients exhibit other specific immunosuppression-independent transcriptomic profiles.

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