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

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.

Biomarkers of Tolerance in Kidney Transplantation: Are We Predicting Tolerance or Response to Immunosuppressive Treatment?

“…Edemir et al 18 used a rodent model to describe gene expression patterns that support the spontaneous simultaneous activation of immune effector–related pathways and protective and immune counter‐regulatory mechanisms as a response to the allogeneic transplant. In humans, we and others have previously described a dysregulation of B cell–related genes in tolerant recipients—associated with the maintenance or expansion of transitional B cells in peripheral blood 8, 9—that elicited new avenues toward understanding the role of transitional B cells in tolerance 19, 20, 21. Differential expression profiles associated with IS treatment have been demonstrated by Erickson et al 22 in the context of transplantation in rats.…”

“…A number of studies, including our own, have suggested gene expression signatures of tolerance in kidney transplantation 7, 8, 9, 11, 32 or have described differential expression of smaller gene sets 11, 33, 34. None had assessed the confounding effect of IS.…”

Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation

“…Although spontaneous immune tolerance in recipients in the case of kidney transplant is rare [81], immune tolerance to allografts can be achieved by three main mechanisms: clonal deletion, anergia and immune regulation. Hematopoietic stem cells were the first cell type assessed in patients for the induction of chimerism and subsequent allograft tolerance [82], but this approach is associated with graft versus host disease (GVHD), humoral rejection and graft loss in some cases [83].…”

Tolerance--Is It Worth It?

“…Approximately 100 cases of operational tolerance in renal transplant have been reported (Orlando et al 2010) with a denominator of many tens of thousands of total kidney transplants. There are a steadily increasing number of reports of different immune monitoring phenotypes or "signatures" that characterize tolerant recipients (Brouard et al 2005Newell and Larsen 2006;Einecke et al 2010;Newell et al 2010;Sagoo et al 2010). It may be possible to use these combined signatures to identify candidates for immunosuppression weaning.…”