Tolerogenic Mechanisms in Liver Transplantation

Abstract

SOJ Immunology Open Access Review Article incidence of rejection compared with other solid organs, and spontaneous acceptance of the liver graft with successful discontinuation of immunosuppression has been reported in nearly 20% of LT recipients [10,11]. Multiple studies have suggested the protective effect of the liver allograft in Simultaneous Liver-Kidney Transplantation (SLKT) compared with recipients of isolated renal transplants; SLKT recipients demonstrate a lower frequency of kidney rejection as well as improved long-term survival [12-14]. Among sensitized kidney transplant recipients with positive lymphocytotoxic crossmatches, inclusion of the liver graft reverted the crossmatch to negative within 1 hour of reperfusion, and prevented the occurrence of hyperacute rejection [15,16]. The protective effect of simultaneous LT extends to other solid organ grafts, as the observed incidence of intestinal allograft rejection is reduced in combined liver-intestine transplant recipients [17]. Various mechanisms have been proposed for the immunomodulatory properties of the transplanted �liver (Figure 1). It has been shown that the liver harbors donor-derived hematopoietic cells, called passenger leukocytes, which are transferred to the recipient at the time of transplantation. Donor microchimerism, or the persistence of donor cells and nucleic acid in the blood and tissues of the recipient, has been postulated to promote long-term graft survival. Hepatocytes and nonparenchymal cells within the liver are thought to play an important role in the modulation of the T cell response which contributes to tolerance. An alternative hypothesis suggests that the large size of the liver graft creates a high antigen dose which overwhelms the recipient alloimmune response. Another attractive theory involves the absorption and/or neutralization of alloreactive antibodies by the membrane-bound and soluble forms of Major Histocompatibility Complex (MHC) class I molecules introduced by the liver allograft. In this review, we will examine the experimental and clinical evidence underlying each hypothesis, and integrate these concepts for an enhanced understanding of transplantation tolerance. Passenger leukocytes and donor microchimerism The 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 Absract The 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 donor-derived 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.