Defining a Methylation Signature Associated With Operational Tolerance in Kidney Transplant Recipients.

Ramon M Rodriguez,Eliecer Coto,Antonio López-Vázquez,Carmen Díaz-Corte,Isabel Mendizabal,Carlos López-Larrea,Ana M Aransay,María Luisa Suarez-Fernandez,Ana R Cortazar,Juan José Lozano,María Laura Saiz,Beatriz Suarez-Álvarez,Viviana Corte-Iglesias,María P Hernández-Fuentes

doi:10.3389/fimmu.2021.709164

Abstract

Operational tolerance after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. We performed genome-wide analysis of DNA methylation in peripheral blood mononuclear cells from kidney transplant recipients with chronic rejection and operational tolerance from the Genetic Analysis of Molecular Biomarkers of Immunological Tolerance (GAMBIT) study. Our results showed that both clinical stages diverge in 2737 genes, indicating that each one has a specific methylation signature associated with transplant outcome. We also observed that tolerance is associated with demethylation in genes involved in immune function, including B and T cell activation and Th17 differentiation, while in chronic rejection it is associated with intracellular signaling and ubiquitination pathways. Using co-expression network analysis, we selected 12 genomic regions that are specifically hypomethylated or hypermethylated in tolerant patients. Analysis of these genes in transplanted patients with low dose of steroids showed that these have a similar methylation signature to that of tolerant recipients. Overall, these results demonstrate that methylation analysis can mirror the immune status associated with transplant outcome and provides a starting point for understanding the epigenetic mechanisms associated with tolerance.

Highlights

The Kidney transplantation is the most suitable treatment for end-stage renal disease
Our results indicate that DNA methylation changes are associated with transplant outcome, and that operational tolerance is associated with the acquisition of different methylation profiles in genes related to B and T cell signatures, which could condition the immune response mediated by these cell types
In order to study the methylation dynamics in peripheral blood associated with operational tolerance, we performed wholegenome DNA methylation analysis in Peripheral blood mononuclear cells (PBMCs) from kidney transplant recipients (KTR) with operational tolerance (TOL; n = 9), chronic rejection (CR; n = 6), and healthy controls (HC; n = 7) (Table 1)

Summary

Introduction

The Kidney transplantation is the most suitable treatment for end-stage renal disease. There is no efficient tolerance-inducing protocol, because of the high risk of rejection associated with IS withdrawal and the difficulty of predicting transplantation outcome. In this context, it is essential to develop reliable noninvasive biomarkers to identify potentially tolerant patients and to minimize IS drugs. It is essential to develop reliable noninvasive biomarkers to identify potentially tolerant patients and to minimize IS drugs With this aim, gene expression studies using microarray technology have generated transcriptional signatures associated with operational tolerance [4,5,6]. Identifying the epigenetic networks in peripheral blood of KTR could yield new insights into the immune mechanisms associated with operational tolerance

Methods

Results

Discussion

Conclusion