Reconsidering the detection of tolerance to individualize immunosuppression minimization and to improve long-term kidney graft outcomes

In kidney transplantation, minimizing the side effects of the immunosuppressive regimen and inducing tolerance to allograft are the two main objectives to improve outcome. At present, these objectives are far from being achieved and remain elusive for the majority of transplant recipients. Rejection rate and mortality on the long term are still unacceptable. There is thus a pressing need to improve this situation. Therefore, some spontaneously tolerant kidney recipients are described in clinics, and recent advances in immunological and molecular techniques have led to a resurgence of interest in studying those rare transplanted recipients through coordinated efforts from international consortia. Indeed, they offer, on the one hand, the possibility to develop specific biomarkers indicative of this state that would constitute a major advantage in the care of the patients allowing personalized minimization of drugs, so reducing related costs and side effects. On the other hand, they represent a unique model of study to understand the mechanisms of regulation implicated in this state that may help the development of inducing therapies. Recent efforts, concentrated on noninvasive analyses of peripheral blood, identified a predominance of several B-cell subsets, some of which harbouring regulatory functions, and related marker genes. These findings, validated in independent multicentric cohorts, led credence to an unsuspected role for the B-cell compartment in tolerance to kidney allograft. The identification of patients, harbouring these markers, among immunosuppressed recipients with stable graft function and the existence of drugs with selective effect on B cell pave the way for the possibility to improve long-term graft outcomes. Therefore, before routine application, these findings need to be confirmed in large prospective studies in the context of planned reduced immunosuppression.