Tolerogenic Mechanisms in Liver Transplantation

Passenger Leukocytes and Donor MicrochimerismThe liver contains large numbers of donor-derived passenger leukocytes which migrate out of the graft immediately after transplantation and can persist in the recipient for some time AbsractThe liver has unique tolerogenic properties which have been recognized since the beginning of liver transplantation.The liver allograft not only demonstrates a lower incidence of rejection compared with other solid organs, but it also has the ability to protect other organs from the same donor against rejection and graft loss.Up to 20% of liver transplant recipients have been successfully weaned from immunosuppressive therapy while maintaining stable allograft function.Furthermore, the liver has the ability to reverse ongoing rejection of other transplanted organs and counters the deleterious effects of preformed lymphocytotoxic antibodies.Various mechanisms have been proposed to explain the immunomodulatory properties of the liver.These include: (1) the transfer of donorderived hematopoietic cells, called passenger leukocytes, with the liver graft and the creation of donor microchimerism; (2) the role of hepatocytes and non-parenchymal liver cells as tolerogenic antigen presenting cells; (3) the high-dose antigen effect leading to dilution of cytokines and clones of alloreactive T cells; and (4) the introduction of soluble and cell-bound major histocompatibility complex class I molecules by the liver graft.This article will examine the evidence underlying each of these hypotheses and assess their relative significance in the induction and maintenance of donor-specific hyporesponsiveness.An enhanced understanding of the immune processes responsible for transplantation tolerance may lead to the identification of biomarkers for the prediction of graft outcomes.More importantly, this knowledge may facilitate the development of therapeutic strategies to promote indefinite allograft acceptance, while eliminating or minimizing the need for immunosuppressive drugs.