Identification of a B cell signature associated with renal transplant tolerance in humans

TLDR

Allograft tolerance—long‑term graft acceptance without continuous immunosuppression—is a highly desirable goal in solid organ transplantation. The study aimed to identify biomarkers that predict which renal transplant recipients could safely withdraw or minimize immunosuppression. Researchers assembled the largest known cohort of tolerant recipients (stable graft function, >1 year off immunosuppression) and compared their gene‑expression profiles and peripheral blood lymphocyte subsets to those of stable, drug‑treated recipients and healthy controls. Renal tolerance was strongly associated with a distinct B‑cell transcriptional signature, including upregulated B‑cell differentiation genes, a 3‑gene panel that distinguished tolerant from non‑tolerant patients, and increased CD20 mRNA in urine cells and peripheral naive/transitional B cells, highlighting a key B‑cell role and providing candidate genes for broader screening.

Abstract

Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.