Gadolinium chloride suppresses acute rejection and induces tolerance following rat liver transplantation by inhibiting Kupffer-cell activation

Abstract

The aim of the present study was to investigate the mechanism by which gadolinium chloride (GdCl3) inhibits Kupffer cell (KC) activation and its ability to suppress acute rejection and induce tolerance following liver transplantation in rats. Rats were randomly divided into control, liver transplantation with GdCl3 pretreatment and liver transplantation with normal saline pretreatment groups. The survival rate, liver function, hepatic pathological histology, cytokine levels in the liver and bile, activity of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in KCs, and expression levels of membranous molecules on the KCs were observed. It was identified that the one-month survival rate in the GdCl3 group was significantly higher compared with that in the saline group (P<0.05). The liver function in the GdCl3 group gradually recovered following transplantation surgery; however, it progressively deteriorated in the saline group. There were minor changes of hepatic pathological histology in the GdCl3 group, whereas changes typical of acute rejection occurred in the saline group. In the GdCl3 group, the levels of interferon γ and interleukin (IL)-2 were significantly lower whereas the levels of IL-10 were significantly higher compared with those in the control and saline groups (all P<0.01). The IL-4 levels in the GdCl3 and control groups were similar. The activity of NF-κB in the saline group was significantly higher compared with those in the control and GdCl3 groups (P<0.01). The expression levels of major histocompatibility complex-II, cluster of differentiation (CD)80 and CD86 on the KC membranes in the GdCl3 group was significantly lower compared with those in the control group (P<0.05); however, these membranous proteins were highly expressed in the saline group. These data indicate that GdCl3 efficiently inhibits the immunological activity of KCs, suppresses acute rejection and induces tolerance following liver allograft transplantation in rats.

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms

“…An intriguing direct strategy involves use of gadolinium chloride to inhibit KC activation. This drug has shown promise in animal models of liver transplantation where administration of gadolinium chloride reduced markers of liver injury and improved hepatic blood flow . Unfortunately at this time, no correlative human data exist.…”

The CD8 T‐cell response during tolerance induction in liver transplantation

“…115 However, other studies have found a beneficial outcome on liver allograft survival after gadolinium chloride treatment in other animal models. 116, 117 In mice, deletion of KCs with clodronate liposomes in donor liver allografts does not affect their acceptance. 118 …”

“…115 However, other studies have found a beneficial outcome on liver allograft survival after gadolinium chloride treatment in other animal models. 116,117 In mice, deletion of KCs with clodronate liposomes in donor liver allografts does not affect their acceptance. 118 Immunoregulatory mechanisms to maintain long-term tolerance in the liver Mechanisms that establish tolerance immediately after transplantation are sufficient to prevent early graft rejection, but may not Role of Tregs and other regulatory mechanisms.…”

Influence of Hepatectomy on Body Temperature Change in Rats

“…The dose of gadolinium chloride used in this study showed no toxicological effects when injected intravenously into rats 10,11 . Both agents were purchased from R & D Systems, Inc. Minneapolis, MN, USA as preservative-free reagents.…”