Mechanisms of disease: the evolving understanding of liver allograft rejection

Liver transplantation is a successful treatment for select forms of liver disease and is unrivalled amongst other forms of solid organ transplantation in the ability of the recipient to develop long-term tolerance to the allograft. Much of this success can be attributed to the inherently tolerogenic manner in which antigens are presented in the liver and the presence of specialized regulatory lymphocyte populations. These observations are not universal, however, and a proportion of recipients develop problematic allograft rejection. Anti-allograft responses lead to an influx of effector cells that target hepatic parenchymal cells and induce apoptosis through members of the tumor necrosis factor superfamily. Anti-rejection therapies have traditionally targeted the entire lymphocyte response against the allograft and, whilst these therapies have been efficacious at limiting effector cell responses, they have also had deleterious effects on the regulatory cell populations that are required to promote long-term tolerance. The emergence of newer anti-rejection drugs that have the potential to target the effector response selectively, whilst preserving the much needed tolerogenic responses, has afforded us the opportunity to refine our future immunosuppressant strategies.