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. (HEPATOLOGY 2006;43:S151-S163.)

Acquired immunologic tolerance: with particular reference to transplantation

“…Inexplicably, no comparable cohort of drug-free kidney recipients was produced again, anywhere in the world, in the next 4 decades. [5] Hepatic ''tolerogenicity'' However, drug-free human recipients of cadaveric liver grafts continued to be observed, some of whom have been off all immunosuppression for more than 30 years [5,6]. Importantly, such liver recipients were produced only in three historical periods during which light immunosuppression was used [7].…”

Kupffer cell heterogeneity: functional properties of bone marrow–derived and sessile hepatic macrophages

“…35,36 A further complication is that transplant recipients are usually treated with immunosuppression to prevent rejection of the graft. 37 The influence of any of these events on KC dynamics is hard to predict.…”

Individual Stability of Stereotypes of Immune Reacting and Modern Possibilities of Their Diagnostic in Organ Transplantation (Immune-Physiological Analysis of a Problem)

“…Современный опыт трансплантации органов подтверждает, что реципиенты действительно неоди-наково реагируют на аллотрансплантат. После срав-нительно короткого периода адаптации с помощью иммуно-супрессивных препаратов [5] одна часть ре-ципиентов способна выйти на толерантность и не от-торгать трансплантат при отмене иммуносупрессии (например, толерантность к трансплантату печени у детей достигает 60% [3,4,6], у взрослых -20% [2,7], тогда как у большей части реципиентов избежать от-торжения удается лишь при постоянном применении медикаментозной иммуносупрессии [5,8].…”