The unfinished legacy of liver transplantation: emphasis on immunology

Abstract

Liver transplantation radically changed the philosophy of hepatology practice, enriched multiple areas of basic science, and had pervasive ripple effects in law, public policy, ethics, and theology. Why organ engraftment was feasible remained enigmatic, however, until the discovery in 1992 of donor leukocyte microchimerism in long-surviving liver, and other kinds of organ recipients. Following this discovery, the leukocyte chimerism-associated mechanisms were elucidated that directly linked organ and bone marrow transplantation and eventually clarified the relationship of transplantation immunology to the immunology of infections, neoplasms, and autoimmune disorders. We describe here how the initially controversial paradigm shift mandated revisions of cherished dogmas. With the fresh insight, the reasons for numerous inexplicable phenomena of transplantation either became obvious or have become susceptible to discriminate experimental testing. The therapeutic implications of the "new immunology" in hepatology and in other medical disciplines, have only begun to be explored. Apart from immunology, physiologic investigations of liver transplantation have resulted in the discovery of growth factors (beginning with insulin) that are involved in the regulation of liver size, ultrastructure, function, and the capacity for regeneration. Such studies have partially explained functional and hormonal relationships of different abdominal organs, and ultimately they led to the cure or palliation by liver transplantation of more than 2 dozen hepatic-based inborn errors of metabolism. Liver transplantation should not be viewed as a purely technologic achievement, but rather as a searchlight whose beams have penetrated the murky mist of the past, and continue to potentially illuminate the future.

Fig. 1

Contemporaneous host-versus-graft (HVG) and graft-versus-host (GVH) immune responses after transplantation. The presence of the weaker GVH response in organ recipients (the inverted curves on a gray background) was not recognized until the discovery of microchimerism in 1992.^, However, the demonstration in 1962–63 that the HVG response (rejection) is reversible and may be succeeded by a state of variable tolerance (yellow panel) allowed the practical development of immunosuppression-aided clinical organ transplantation.

Fig. 2

The consequences of antigen spread and localization (see text): (A) with liver or other kinds of organ transplantation; (B) with a viral hepatitis infection; (C) with a human immunodeficiency virus (HIV) infection; (D) with a pulmonary cytomegalovirus infection.

Fig. 3

Organ-induced tolerance. (A) Spontaneous tolerance induced by the liver in experimental models^–,– in which the host-versus-graft immune response induced by the migratory donor leukocytes is too weak to eliminate the donor antigen and is exhausted and deleted (the rise and fall of the continuous thin line). Maintenance of engraftment depends on small numbers of persistent donor leukocytes (microchimerism). The less well–leukocyte-endowed heart and kidney also can “self- induce” engraftment but in a much smaller number of models. (B) Immunosuppression-aided tolerance in organ transplantation models in which the recipient response that normally would cause rejection (dashed line) is reduced into a deletable range (continuous thin line) with a short course of early post-transplantation immunosuppression. Lifetime tolerance after stopping immunosuppression was first convincingly demonstrated in canine liver recipients. (C) A self-defeating consequence of excessive prophylactic over-immunosuppression (depicted with multilayered bars) that subverts efficient clonal exhaustion- deletion. The initially over-treated recipient may be committed to unnecessarily high maintenance immunosuppression. This undesirable effect of too much immunosuppression was not recognized until 2001. Tx = Transplantation

Fig. 4

Protocol of “tolerance friendly” immunosuppression introduced at the University of Pittsburgh Medical Center. An antilymphoid antibody infusion before arrival of an allograft reduces the anticipated antidonor response into a more readily deletable range and allows maintenance treatment to begin with daily monotherapy to which other agents are added only for rejection. Weaning from the monotherapy may be possible later. The inverted curve at the bottom shows the usually silent graft-versus-host (GVH) reaction shown more clearly in Figure 1. Tx, transplantation

Fig. 5

An example of the strategy shown in Fig. 4. A woman with a hepatic hemangioendothelioma who was infused with 5 mg/kg antithymocyte globulin (ATG, thymoglobulin) before liver allograft revascularization. Tacrolimus (TAC) monotherapy was reduced from daily to every other day at 100 days, and to once per week by 10 months. Treatment was stopped at 22 months. She has been immunosuppression-free for 11/2 years. Serum bilirubin and measures of hepatic parenchymal function have been normal throughout. Although enzyme levels have been stable, these have hovered at a high normal range or slightly above since a rejection at 6 months, which was treated with 1 g methylprednisolone. SGOT: serum glutamic-oxaloacetic transaminase, GGTP: gamma-glutamyl transpeptidase.

Fig. 6

Patient and graft survival (above), and current immunosuppression (below) of hepatitis-free primary liver transplant recipients treated in Pittsburgh with the principles of immunosuppression shown in Fig. 4, and exemplified in Fig. 5. Left: pretreatment was with an infusion of 5 mg/kg rabbit ATG (thymoglobulin) (n = 23). Right: pretreatment was with 30 mg alemtuzumab (Campath^®) (n = 38).

Fig. 7

The 35 patients from the first 210 who survived 25 years or longer after liver replacement at the University of Colorado (n = 184) or University of Pittsburgh (n = 26). The times on (red) and off immunosuppression (green) in individual patients are displayed in the horizontal bars. Note that 6 of the 32 still-surviving recipients had retransplantation 11 to 28 years after the primary procedure.

Fig. 8

The relation of organ-induced engraftment (right) to classical models of spontaneous donor leukocyte chimerism-associated tolerance.