Tolerance in liver transplantation: Biomarkers and clinical relevance

Abstract

Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as “operational tolerance”. However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.

Differential profile of activated regulatory T cell subsets and microRNAs in tolerant liver transplant recipients

“…Many studies have emphasized the genetic and phenotypic profile of blood or tissue samples from tolerant transplant patients. This approach has given great results, overall clarifying the involvement of FOXP3 + Tregs in this phenomenon beyond other actors such as B cells, natural killer cells, and γδTCR cells as well as liver iron metabolism . However, it is well established that Tregs are not a homogeneous subset of cells.…”

Transplant Tolerance Induction: Insights From the Liver

“…The dynamic profile of Treg in liver transplant recipients during IS weaning was explored by monitoring the frequency of Treg and Foxp3 mRNA expression in PBMC in 12 liver transplant patients undergoing IS withdrawal. A progressive increase in circulating CD4 + CD25 + Foxp3 + Treg and Foxp3 mRNA expression was associated with operational tolerance in liver transplant recipients (14,116). The expression of adenosine deaminase, which degrades adenosine to evoke stronger Treg activation, was higher in five tolerant liver transplant patients compared to the 12 non-tolerant recipients.…”

“…Liver pDC prevent oral T cell priming through inducing anergy or deletion of circulating T cells via a CD4 + T cell-independent mechanism (11). Monocytes cultured with hepatocyte growth factor or liver epithelial cells can differentiate into DC that release high levels of IL-10 (12, 13), suggesting that the hepatic microenvironment modulates DC differentiation into regulatory subsets (14).…”

Biomarkers of immune tolerance in liver transplantation

“…Tolerogenic plasmacytoid DCs have a low capacity for T cell stimulatory functions and a high capacity for inducing tolerogenicity, mainly through downregulation of MHC class II and costimulatory molecules, upregulation of inhibitory factors and secretion of effector molecules and regulatory cytokines (e.g. nitric oxide, IL-10) [47]. In the context of SOT LT recipients, plasmacytoid DCs were observed at higher frequencies in some [48], but not all analyses [44].…”