Clinical Potential of Regulatory T Cell Therapy in Liver Diseases: An Overview and Current Perspectives

Abstract

The increasing demand for liver transplantation and the decline in donor organs has highlighted the need for alternative novel therapies to prevent chronic active hepatitis, which eventually leads to liver cirrhosis and liver cancer. Liver histology of chronic hepatitis is composed of both effector and regulatory lymphocytes. The human liver contains different subsets of effector lymphocytes that are kept in check by a subpopulation of T cells known as Regulatory T cells (Treg). The balance of effector and regulatory lymphocytes generally determines the outcome of hepatic inflammation: resolution, fulminant hepatitis, or chronic active hepatitis. Thus, maintaining and adjusting this balance is crucial in immunological manipulation of liver diseases. One of the options to restore this balance is to enrich Treg in the liver disease patients. Advances in the knowledge of Treg biology and development of clinical grade isolation reagents, cell sorting equipment, and good manufacturing practice facilities have paved the way to apply Treg cells as a potential therapy to restore peripheral self-tolerance in autoimmune liver diseases (AILD), chronic rejection, and posttransplantation. Past and on-going studies have applied Treg in type-1 diabetes mellitus, systemic lupus erythematosus, graft versus host diseases, and solid organ transplantations. There have not been any new therapies for the AILD for more than three decades; thus, the clinical potential for the application of autologous Treg cell therapy to treat autoimmune liver disease is an attractive and novel option. However, it is fundamental to understand the deep immunology, genetic profiles, biology, homing behavior, and microenvironment of Treg before applying the cells to the patients.

Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury

“…IDO‐mediated regulation of tryptophan metabolism is a highly versatile modulator of cellular immunity . IDO converts tryptophan to kynurenine, which inhibits the proliferation of effector T cells, but promotes expression of Treg lineage‐defining transcription factor FOXP3 . In line with these findings, injection of MSCs or MSC‐CM significantly increased the total number of liver Tregs (Fig.…”

“…Tregs are residing in the liver where they have a crucial role in the maintenance of immunologic tolerance . As a result of the decreased number of intrahepatic Tregs, the liver rapidly switches from an immune privilege organ into the organ enriched with the inflammatory and hepatotoxic cells .…”

“…3C,D). Accordingly, repopulation of intrahepatic Tregs is a crucially important step for the attenuation of acute liver inflammation . MSCs are able to promote induction and expansion of Tregs in vitro .…”

Changes in natural killer cells and exhausted memory regulatory T Cells with corticosteroid therapy in acute autoimmune hepatitis

“…In parallel to an increase in NK cell frequency, we also observed an increased Treg frequency in the circulation of patients with treatment‐naive AIH. Tregs are crucial to maintain peripheral immune tolerance and control effector immune cells . The increase in the Treg population may thus be an attempt to suppress immune activation stimulated by the causative autoantigen in acute AIH.…”

“…Tregs are crucial to maintain peripheral immune tolerance and control effector immune cells. (37,38) The increase in the Treg population may thus be an attempt to suppress immune activation stimulated by the causative autoantigen in acute AIH. Although both NK bright and Treg cell frequencies were increased in treatment-naive patients, the Treg versus NK bright cell ratio was reduced, suggesting a skewing of the immune balance toward the effector arm in the treatment-naive state.…”