The translational approach to liver transplantation

GENTILINI, M. VIRGINIA; BENITEZ, P. CONSTANZA ARRIOLA; GONDOLESI, GABRIEL E.

ANNALS OF HEPATOLOGY

MEXICAN ASSOC HEPATOLOGY

Año: 2022 vol. 27

1665-2681

Liver transplantation has proved to be a successful life-savingtreatment for end-stage liver diseases. Yet, despite the remarkableprogress made since the first successful human liver transplant,many open questions still need to be addressed. The solution for anumber of current issues requires the implementation of adequateresearch programs as part of the clinical agenda. However, the process of bringing basic science knowledge into clinical practiceremains a challenge. The need to potentiate the development ofinnovative discoveries capable of improving human health hasopened the doors to new possibilities for experts and programs.Salient among them is the opportunity to establish a multi-stepprocess for transforming observations in the clinic, laboratoriesand the community into interventions that enhance people's livesthrough diagnostic, therapeutic, procedural, device and behavioralchanges that have been designated as translational research andscience [1,2]. This type of research has found transplantation tobe a fertile ground for development; transplantation and translational science call for and encourage multidisciplinary collaborations to identify and support the adoption of more effectivemedical practices for the benefit of patients requiring novel andunique therapeutic approaches [1,2].Over the last decades, liver transplantation has benefited fromtranslational research programs. We will expand on two areas ofresearch aimed at maximizing the use of scarce organ resources byminimizing the risks of losing transplanted organs: one concerns thereduction of graft rejection, while the other seeks to expand the poolof available organs utilizing novel preservation technologies.The liver is the largest solid organ in the body. In addition to itsclassical, widely described functions in metabolism, detoxification andnutrient storage, it has been recognized as a unique immunologicalorgan characterized by a tolerogenic microenvironment. [3] Nonetheless, despite its well-known immunotolerant properties, hepatic allografts are susceptible to cellular and antibody-mediated rejection. Themechanisms involved in hepatic tolerance and rejection are as yetonly partially understood; further insight is required not only into theinteraction between hepatocytes, non-parenchymal cells and immunecell populations, but also into the underlying molecular signaling pathways that govern these phenomena. The cytokine IL-33 and its specificreceptor (ST2) play important roles in organ transplantation [4,5].Studies have shown that the IL-33/ST2 pathway takes part in thedevelopment of liver pathology [6−8], but its function in liver transplantation remains obscure. Our research group is currently focusedon the study of the IL-33/ST2 axis during allograft rejection, fibrosisand liver injury in the transplant context as part of our translationalresearch program [manuscript in preparation].Early works on immunosuppressive drugs discovered and established the association between calcineurin inhibitors and other drugssuch as the backbone regimes used for most organs including theliver [9]. However, given the adverse effects caused by the long-termuse of immunosuppression and the lack of new drugs in the pipeline,cell therapies have been proposed in the translational field as a promising tool for controlling the alloimmune response in transplantpatients. Several cell types with immunomodulatory properties havebeen evaluated in preclinical models and phase I clinical trialsfocused on CD4+ regulatory T-cells, with results confirming their safeand feasible usage (Tregs). Todo S. et al. investigated the adoptivetransfer of ex-vivo-generated Treg-enriched products in 10 consecutive adult patients undergoing living-donor liver transplantation. Thetherapy proved to be safe, with seven recipients successfully stoppingimmunosuppression for nearly two years [10]. More recently,Sanchez-Fueyo et al. performed an open-label, dose-escalating phase I clinical trial, demonstrating that using ex-vivo expanded autologouspolyclonal Tregs in adult liver transplant recipients was safe, did notincrease the incidence of infections or cancer, and appeared to induceanti-donor-specific hyporesponsiveness [11].Over the past few years, several researchers have been engineering chimeric antigen receptor (CAR)-Tregs to produce donor antigenspecific Tregs [12] Experiments in animal models have demonstratedthat CAR-Tregs reduce alloimmune responses more effectively thanpolyclonal Tregs in skin humanized models and prevent xenogeneicGVHD [13,14]. The evolution from transferring polyclonal Tregs tothe recipient to producing alloantigen-specific CAR-Tregs providesan example of a promising translational strategy for achieving tolerance; nonetheless, further studies are required to more conclusivelydefine the applicability, safety and efficacy of using CAR-Tregs inhuman liver transplantation worldwide.