The liver is a vital organ that plays myriad roles for the survival of human life as it controls and affects various metabolic and physiological regulatory processes in the body. These processes include protein synthesis, carbohydrate and fat metabolism, blood clotting, immune system, hormonal responses, detoxification (alcohol, chemical toxins, and drugs), and waste removal. Any kind of damage to the liver can lead to several complications that can affect the functioning of other organs.
Several artificial approaches such as plasmapheresis, hemodialysis, plasma exchange, filtration, and hemoperfusion. However, these approaches showed limited success as a result of the insufficient replacement of all the metabolic functions of the liver and the lesser number of viable non-damaged liver cells.
Liver transplantation is the definitive treatment strategy for patients with end-stage liver disease such as alcoholic liver disease, idiopathic/autoimmune liver disease, acute liver failure, hepatitis B or hepatitis C Virus infection, metabolic liver disease or cancers. Over the decades, there has still been remarkable improvement in the surgical technique and the types of immunosuppressive drugs for managing liver transplantation in order to prolong recipient survival.
Short-term outcomes following transplantation have improved immensely. Long-term outcomes still prevail due to the very medications that gave such favorable early survival rates following transplantation. The causes of long-term morbidity and mortality after transplantation appear to be non-hepatic and are either directly or indirectly linked to the necessary long term administration of non-specific immunosuppressive drugs which can lead to cardiovascular disease, diabetes, infection, malignancy, and renal disease.
The immunological tolerance of the liver:
Many scientists are aiming to utilise the inherent immune tolerance of the liver to avoid using excessive amounts of immunosuppressive medication.
The host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Chronic rejection has a complex and only partly understood etiology which is probably why the current therapies for preventing it are, although effective, still cause side-effects.
The processes that induce immune tolerant properties in transplantation in the liver are not fully understood and various hypotheses have been put forward. The location of the is such that it receives 75% of its blood flow from the gastrointestinal tract, spleen, and its associated organs. While the intestinal mucosa acts as a primary barrier against microbial translocation it is by no means impenetrable.
Due to its close proximity with the gastrointestinal region, the liver is constantly subjected to antigen and endotoxin stimulation via portal venous circulation. To manage this antigen load, the liver is equipped with various specialized cells such as hepatocytes, Kupffer cells, liver sinusoidal endothelial cells (LSEC), liver-specific dendritic cells (DCs), and stellate cells. These cells form an intricate infrastructure within the organ that interacts with circulating lymphocytes thus helping to strike a balance between defensive immune responses against harmful antigens and immune tolerance against self antigens.
These cells act as effective antigen-presenting cells (APC) for T-Lymphocytes. The interactions between the liver APCs and T-cells downregulate the production of co-stimulatory molecules and prevent T-cell activation, and recruit T-regulatory cells to reduce any autoimmune response.
Another hypothesis surrounding the liver’s unique tolerogenic qualities in transplantation is microchimerism by donor passenger leukocytes. Following transplantation, there is a migratory exchange of leukocytes between the graft and the recipient. Passenger leukocytes from the transplanted liver travel out into the recipient’s blood stream and persist for a considerable amount of time thereafter developing a state of microchimerism.
These passenger leukocytes infiltrate the lymphoid tissue and induce a powerful immune response such as T-cell activation. This produces large quantities of proinflammatory cytokines that paradoxically, kills T lymphocytes through apoptosis, thus preventing the immune system from over-responding to the donor’s antigens. Another rationale takes into account the size of the liver. The liver is the largest transplanted organ with significant tissue antigen mass which is hypothesised to dilute the cytokines and alloreactive T-lymphocytes, in turn exhausting recipient immune responses.
Reports of patients post liver transplantation acquiring “operational” tolerance can be attributed to these tolerogenic qualities of the liver. This highlights the potential for withdrawing immunosuppressive medication in the absence of graft rejection and thus a drug-free transplantation.