The mystique of hepatic tolerogenicity

The evolution of clinical transplantation has hinged on 2 seminal turning p oints. The first was the demonstration in 1953 by Billingham, Brent, and Me dawar that chimerism-associated tolerance could be induced deliberately in neonatal mice by infusing adult donor hematolymphopoietic cells. This disco very escalated in a straight line over the next 15 years to successful bone marrow transplantation in humans. The second turning point was the demonst ration that organ allografts could self-induce tolerance under an umbrella of immunosuppression, or in some species without immunosuppression. Unfortu nately it was incorrectly concluded by most immunologists and surgeons that bone marrow and organ engraftment involved different immune mechanisms. In a derivative error, it became widely believed that the tolerogenicity of t he liver differed fundamentally not only from that of bone marrow but also from that of other whole organs. These errors became dogma and were not corrected until low level donor leuk ocyte chimerism was found in humans and animals bearing long surviving live r, kidney, heart, and other kinds of allografts. With successfull bone mar- row transplantation, the trace population consisted of recipient lather tha n donor leukocytes. Thus, the consequences of organ and bone marrow engraft ment were mirror images. From these observations, it was proposed that the engraftment of all kinds of organs as well as bone marrow cells (BMC) invol ved host versus graft (HVG) and graft versus host (GVH) reactions with reci procal induction of variable degrees of specific non-reactivity (tolerance) . The maintenance of the tolerance was an active and ongoing process requir ing the persistence of the transplanted fragment of the donor immune system . The immune responsiveness and unresponsiveness to both organ and bone mar row allografts are thought to be governed by the migration and localization of leukocytes. The clarifying principles of transplantation immunology tha t have emerged from the chimerism studies are relevant to the adaptive immu ne response to microbial, tumor allogeneic, and self antigens. These princi ples should be used to guide efforts to systematically induce tolerance to human tissues and organs, and perhaps ultimately to xenografts.