Dataset Information

An exome-wide study of renal operational tolerance.

ABSTRACT:

Background

Renal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients.

Methods

We set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 transplant recipients who maintained good allograft function without immunosuppression for at least 1 year. We performed an exome-wide association study comparing the distribution of moderate to high impact variants in 36 tolerant patients, selected for genetic homogeneity using principal component analysis, and 192 controls, using an optimal sequence-kernel association test adjusted for small samples.

Results

We identified rare variants of HOMER2 (3/36, FDR 0.0387), IQCH (5/36, FDR 0.0362), and LCN2 (3/36, FDR 0.102) in 10 tolerant patients vs. 0 controls. One patient carried a variant in both HOMER2 and LCN2. Furthermore, the three genes showed an identical variant in two patients each. The three genes are expressed at the primary cilium, a key structure in immune responses.

Conclusion

Rare protein coding variants are associated with operational tolerance in a sizable portion of patients. Our findings have important implications for a better understanding of immune tolerance in transplantation and other fields of medicine.ClinicalTrials.gov, identifier: NCT05124444.

SUBMITTER: Massart A

PROVIDER: S-EPMC10230038 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

An exome-wide study of renal operational tolerance.

Massart Annick A Danger Richard R Olsen Catharina C Emond Mary J MJ Viklicky Ondrej O Jacquemin Valérie V Soblet Julie J Duerinckx Sarah S Croes Didier D Perazzolo Camille C Hruba Petra P Daneels Dorien D Caljon Ben B Sever Mehmet Sukru MS Pascual Julio J Miglinas Marius M Pirson Isabelle I Ghisdal Lidia L Smits Guillaume G Giral Magali M Abramowicz Daniel D Abramowicz Marc M Brouard Sophie S

Frontiers in medicine 20230517

<h4>Background</h4>Renal operational tolerance is a rare and beneficial state of prolonged renal allograft function in the absence of immunosuppression. The underlying mechanisms are unknown. We hypothesized that tolerance might be driven by inherited protein coding genetic variants with large effect, at least in some patients.<h4>Methods</h4>We set up a European survey of over 218,000 renal transplant recipients and collected DNAs from 40 transplant recipients who maintained good allograft func ...[more]

PMID: 37265662

Similar Datasets

Project description:Operational tolerance after solid organ transplantation is defined as stable graft acceptance without immunosuppression while maintaining normal immunocompetence against immunological insults. However, it is not clear yet which cellular and molecular pathways are driving tolerance in these patients and how this state can be induced in order to improve graft survival. Several transcriptomic analysis have shown that transcription signatures in blood can reflect the immunological state associated with operational tolerance in kidney transplant. Nonetheless, epigenetic dynamics orchestrating these transcription signatures have not yet been studied. Here, we performed genome-wide analysis of DNA methylation of kidney transplant recipients with chronic rejection and operational tolerance. Our data showed that chronic rejection and operational tolerance recipients have differential DNA methylation in 2737 genes, indicating that each patient group has a specific epigenetic signature associated with transplant outcome. In addition, we observed that operational tolerance is associated with DNA demethylation in genes involved in immune function, including B cell activation (e.g. ST6GAL1, MS4A1 and MEF2C) and the Th17 differentiation program (e.g. LY9 and BATF), while in CR patients is mostly associated intracellular signaling and ubiquitination pathways. Finally, we used weighted gene co-expression network analysis (WGCNA) to select the more defining epigenetic changes associated with operational tolerance. By this method, we select 12 genomic regions specifically hypomethylated (HIVEP2, HOMER1, UTRN, PTPRO, SP100 and JAZF1) or hypermethylated (EMZ8, EZR-AS, WDR20, NADSYN1, TBCD and MED17) in tolerant patients. Analysis of these genes in stable transplant recipients with immunosuppression showed that these patients have a similar methylation signature to operational tolerance recipients. Overall, these results demonstrate that DNA methylation in blood can mirror the immune status associated with kidney transplant outcome and provides a starting point for understanding the epigenetic mechanisms associated with operational tolerance.

Project description:Long-term allograft survival generally requires lifelong immunosuppression. Rarely, recipients display spontaneous operational tolerance with stable graft function in the absence of immunosuppression. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which immunosuppression could be tapered and hinders the development of new tolerance inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and utilize these biomarkers to determine the frequency of this state in immunosupressed patients with stable graft function. Blood gene expression profiles from 75 renal transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on immunosuppression) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a tolerant footprint of 49 genes. These biomarkers were applied for prediction of operational tolerance by microarray and real-time PCR in independent test-groups. 33/49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1/12 and 5/10 stable patients on triple immunosuppression and low dose steroid monotherapy respectively. The gene signature suggests a pattern of reduced co-stimulatory signaling, immune quiescence, apoptosis and memory T cell responses. This study identifies in the blood of kidney recipients a set of genes associated with operational tolerance that may have utility as a minimally-invasive monitoring tool for guiding immunosuppression titration. Further validation of this tool for safe immunosuppression minimization in prospective clinical trials is warranted. 67 samples were analyzed, no replicates included: 1. TOL (n = 12). patients with long-term stable graft function, without immunosuppression for at least 2 years 2. MIS (n = 10). Patients with stable graft function on steroid monotherapy (<10 mg/day) for 4.6. Calcineurin inhibitors and CellCept were removed in these patients because of previous posttransplant lymphoproliferative disease (n = 6), cancer (n = 2), or uncontrolled infectious disease (n = 2). 3. STA (n = 12). Patients with stable kidney graft function at >5 years posttransplantation while under mycophenolate mofetil or azathioprine and maintenance steroids with (n = 5) or without (n = 7) an associated calcineurin inhibitor. 4. AR (n = 14). Patients experiencing rapid decline (>20% from baseline) in graft function and biopsy-proven AR. 5. CR (n = 11). Patients having a progressive degradation of their renal function (creatinine clearance of <60 ml per min per 1.73 m2 and/or proteinuria of >1.5 g/day) and histological signs CR. 6. N (n = 8). These subjects all had normal blood formulae and no infectious or other concomitant pathology for at least 6 months before the study.

Dataset Information

An exome-wide study of renal operational tolerance.

Background

Methods

Results

Conclusion

Publications

An exome-wide study of renal operational tolerance.

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