**1. Introduction**

The past four decades have witnessed the evolution of liver transplantation exploration procedures, and whilst they had witnessed a high mortality and morbidity they now serve as a successful therapeutic measure for end-stage liver disease. Nowadays, one year and five years survival for elective cases are often in excess of 85%-88% and 70%-75% and with an excellent quality of life (Annals of Hepatology, 2010). The remarkable success of liver transplantation is due largely to the development of immunosuppressive regimens that are highly effective at protecting allografts from acute rejection, and which ensure their survival in most cases. Interestingly, early liver transplantation studies with out-bred swine demonstrated that a high percentage of recipients maintained their graft in the absence of immunosuppression (Calne R Y et al., 1969). Subsequently, the spontaneous tolerance of liver allografts was also shown in liver transplantation in several allogeneic rat strain combinations and in most allogeneic mouse strain combinations (Farges O et al., 1995; Dresske B et al., 2002). As such, and compared with other solid-organ transplants, liver allografts have long been considered to be immunologically privileged, as manifest by an absence of hyperacute rejection despite a positive T cell cross-match, a low incidence of graft loss due to chronic rejection, and the potential for hepatocyte regeneration after tissue injury. Finally, in clinical transplantation, there is increasing evidence that some liver transplant recipients who cease taking immunosuppressive drugs maintain allograft function. Despite this special status, the liver can display destructive immunologic processes, since acute liver allograft rejection occurs in approximately 50% to 75% of liver transplant recipients (although in the majority of cases it is readily reversed with immunosuppressive approaches tailored to treat cellular rejection) (covered in a separate CAQ corner). Immunosuppressive drugs, however, also produce significant toxic effects that increase patient morbidity and mortality (Lechler R I et al., 2005; Sayegh M H et al., 2004). Moreover, the current immunosuppressive regimens do not prevent the development of chronic rejection, which is a major cause of graft loss. Most studies have also shown that a variety of autoimmune diseases with unknown aetiologies target the liver, including primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and biliary atresia (Duclos-Vallee J C et al., 2009; Schramm C et al., 2010; Guichelaar MM et al., 2003). As such, compared with other solid-organ transplants, liver transplantation is complex, having a sometimes paradoxical interaction with the host immune system. Understanding these mechanisms is important, as it aids in the understanding of the clinical features of rejection and – hence – in making an early diagnosis and delivering appropriate treatment. Knowledge of these mechanisms is also critical in developing strategies to minimise rejection and in developing new drugs and treatments that blunt the effects of the immune system on transplanted organs, thereby ensuring the longer survival of these organs. The next chapter will elaborate on various aspects of liver transplantation immunology.
