Functional Immune Anatomy of the Liver—As an Allograft

Abstract

The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.

Liver transplantation: Rejection and tolerance

“…In both cases, the presence of a simultaneously transplanted liver appears to reduce the risk of AMR and chronic DSA‐mediated injury significantly in the heart and kidney allografts, when other variables are controlled. Several different mechanisms through which the liver resists DSA‐mediated injury have been postulated, and these have been reviewed elsewhere . However, recent investigations show us that this resistance is not absolute and can be overcome in patients with very high levels of circulating DSA, liver allograft dysfunction, or noncompliance with the immunosuppression.…”

The Role of Humoral Alloreactivity in Liver Transplantation: Lessons Learned and New Perspectives

“…The peribiliary plexus is thought to be derived from hepatic arterial branches and appears exceptionally susceptible to ischemia and immunologic insults [41, 42]. Disruption of the peribiliary plexus by DSA causes arterial insufficiency which, in turn, incurs damage to the biliary epithelium and predisposes to the formation of bile duct strictures [43].…”

“…Following inflammatory insults, class II MHC expression is upregulated on biliary epithelial cells, portal and hepatic artery endothelia, resulting in increased DSA targeting and further immune stimulation. An exhaustive review of the tolerogenic mechanisms and immune reactions within the liver is beyond the scope of this article, and the interested reader is encouraged to refer to an excellent review article written by Demetris et al [41]. …”

Succinct guide to liver transplantation for medical students

“…The safety window may change or fluctuate with time following transplantation. Compared to other solid organ transplants, dosage of immunosuppressants for liver transplant is generally lower probably because the liver is an immune-privileged site much like that of the cornea [24]. Clinicians need to estimate the rejection risk on a case by case basis to achieve adequate degree of immunosuppression at the lowest expense of immunosuppressants to minimize as many side effects as possible, such as renal impairment, neurotoxicity, metabolic syndrome (hypertension, hyperlipidemia, diabetes, hyperuricemia), infection, or malignancy (such as PTLD).…”