Hepatic immune tolerance induced by hepatic stellate cells

Abstract

The liver, which is a metabolic organ, plays a pivotal role in tolerance induction. Hepatic stellate cells (HpSCs), which are unique non-parenchymal cells, exert potent immunoregulatory activity during cotransplantation with allogeneic islets effectively protecting the islet allografts from rejection. Multiple mechanisms participate in the immune tolerance induced by HpSCs, including the marked expansion of myeloid-derived suppressor cells (MDSCs), attenuation of effector T cell functions and augmentation of regulatory T cells. HpSC conditioned MDSC-based immunotherapy has been conducted in mice with autoimmune disease and the results show that this technique may be promising. This article demonstrates how HpSCs orchestrate both innate immunity and adaptive immunity to build a negative network that leads to immune tolerance.

Keywords: Hepatic stellate cells; Hepatic tolerance; Immunotherapy; Myeloid-derived suppressor cells.

Figure 1

Hepatic stellate cells cotransplanted allogeneic islet animal model. Diabetes was induced in recipients with a single intraperitoneal injection of streptozotocin (220 mg/kg body weight). Only mice with nonfasting blood glucose levels exceeding 350 mg/dL were used as recipients. Islets were isolated from donor pancreas by collagenase V. After separation on a Ficoll gradient, the islets were purified by hand picking. Three hundred freshly isolated islets alone or mixed with 1 or 3 × 10⁵ hepatic stellate cells (HpSCs) were aspirated into polyethylene tubing, pelleted by centrifugation for 2 min, and then gently placed under the subcapsular space of the recipient kidney. Transplantation was considered successful if the nonfasting blood glucose returned to and remained normal (< 150 mg/dL) for the first 4 d after transplantation. The tail vein nonfasting blood glucose level was monitored after transplantation, and the first day of 2 consecutive readings of blood glucose levels greater than 350 mg/dL was defined as the date of diabetes onset. No immunosuppressive reagents were administered throughout the experiments.

Figure 2

Immune regulatory functions of hepatic stellate cells. Hepatic stellate cells exert potent immune regulatory mechanisms to prevent immense inflammation in the liver. Hepatic stellate cells (HpSCs) can induce regulatory T cells and inhibit effector T cells responses and the function of APCs. These mechanisms contribute to the unique immune tolerant microenvironment of the liver. DCs: Dendritic cells; MDSCs: Myeloid-derived suppressor cells; Treg: Regulatory T cells; Teff: Effector T cells; ATRA: All-trans retinoic acid; C3: Complement component 3.