Prospects for Immune Tolerance

Introduction

The extraordinary success of liver transplantation (LT) as a treatment for end-stage liver diseases has resulted in the need to redirect research priorities and clinical resources toward improving the health and well-being of what are now thousands of long-term surviving LT recipients. This requires the optimization of pharmacological immunosuppression to prevent immune-mediated liver damage while minimizing toxicity. The routine management of immunosuppressive drugs currently relies on the monitoring of serum liver biochemistry tests and calcineurin inhibitor (CNI) levels. This is despite evidence indicating that these parameters have a poor correlation with pharmacodynamic effects, are insensitive and nonspecific indicators of rejection and liver damage, and do not predict long-term outcomes. The limitations of the current standard of care are perfectly illustrated by the results of immunosuppression withdrawal trials demonstrating that up to 40% of selected liver recipients more than 3 years post-transplant can drastically reduce or even discontinue their immunosuppressive drugs. This phenomenon, known as spontaneous operational tolerance (SOT) , has been described in other solid organ transplant settings as well but is extraordinarily rare outside of LT, which reflects the unique immunoprivileged properties of this organ.

The Liver and the Immune System

The liver provides one of the first lines of defense between the host and external environment. It is exposed to a steady stream of antigens, but it has the unique ability to regulate the nature and intensity of its response. It receives vascular inflow from two separate sources, with approximately 20% being received from the hepatic arteries and the remainder from the portal vein. Upon entering the liver, the arterial and venous blood feeds into the sinusoidal bed. This is a unique capillary network lined by liver sinusoidal endothelial cells (LSECs), channeling blood from the portal tracts into the central vein. The vasculature network differs from other capillary systems because of its low oxygen pressure and a slower velocity of flow, which aids to maximize the contact between circulating molecules and the endothelium. The entering blood is rich in antigens from the native microbiome together with nutritional degradation products. However, despite the influx of these antigens, under normal circumstances, the liver does not mount cytopathic immune responses, but instead, the specialized microenvironment has evolved to exquisitely modulate how the immune system responds. For this reason, the liver has long been considered a tolerogenic organ.

The adaptive immune hyporesponsiveness is best demonstrated by the lack of response to lipopolysaccharide (LPS), which is a membrane component of gram-negative bacteria. In most tissues, toll-like receptors (TLRs) assist in pathogen recognition and removal by activating intracellular signaling cascades upon ligand binding, leading to the production of proinflammatory mediators. LPS is a pathogen recognized by TLRs and is associated with a highly inflammatory response, acting as a pyrogen in vivo and leading to the development of vasoplegic shock. The liver is exposed to high concentrations of LPS via the portal vein, but the concentrations drop over 100-fold between portal blood and peripheral blood. This clearance of LPS takes place without signs of inflammation. The continuous exposure to gut-derived LPS results in upregulation of TLR-signaling inhibitors blocking the production of proinflammatory cytokines and leading to the secretion of antiinflammatory mediators, such as interleukin-10 (IL-10) and transforming growth factor-β.

Both parenchymal (hepatocytes) and nonparenchymal (LSECs, Kupffer cells [KCs], resident lymphocytes, and dendritic cells [DCs]) liver cells are involved in regulating intrahepatic immune responses.