Liver Transplant Tolerance and Its Application to the Clinic: Can We Exploit the High Dose Effect?

Abstract

The tolerogenic properties of the liver have long been recognised, especially in regard to transplantation. Spontaneous acceptance of liver grafts occurs in a number of experimental models and also in a proportion of clinical transplant recipients. Liver graft acceptance results from donor antigen-specific tolerance, demonstrated by the extension of tolerance to other grafts of donor origin. A number of factors have been proposed to be involved in liver transplant tolerance induction, including the release of soluble major histocompatibility (MHC) molecules from the liver, its complement of immunosuppressive donor leucocytes, and the ability of hepatocytes to directly interact with and destroy antigen-specific T cells. The large tissue mass of the liver has also been suggested to act as a cytokine sink, with the potential to exhaust the immune response. In this review, we outline the growing body of evidence, from experimental models and clinical transplantation, which supports a role for large tissue mass and high antigen dose in the induction of tolerance. We also discuss a novel gene therapy approach to exploit this dose effect and induce antigen-specific tolerance robust enough to overcome a primed T cell memory response.

Innovative approach in Pompe disease therapy: Induction of immune tolerance by antigen-encapsulated red blood cells

“…However, contrasting with data obtained with the OVA antigen, the level of AGA-specific humoral response inhibition was not directly related to the quantities of AGA encapsulated in RBCs. As the dose of antigen used in tolerance induction seems to be an important factor in success (Cunningham et al, 2013;Hilliard et al, 2000), several quantities of AGA encapsulated in RBCs were tested. A better decrease in specific humoral response was obtained with a 40-65 mg of AGA encapsulated in RBCs (>10-fold decrease of AGAspecific IgG).…”

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

“…As mentioned above, the main challenge considering liver transplantation is minimization of immunosuppression with the goal of donor-specifi c tolerance (Fung 1999 ). Liver graft acceptance results from donor antigen-specifi c tolerance which is demonstrated by the extension of tolerance to other grafts of donor origin (Cunningham et al 2013 ). In other words co-transplantation of a liver allograft can prevent rejection of other organ grafts from the same donor (Rasmussen et al 1995 ;Kamada and Wight 1984 ).…”

“…Actually the underlying mechanisms of spontaneous liver transplant tolerance are not known precisely. Several factors have been proposed for the ability of the transplanted liver to be spontaneously accepted by the recipient (Cunningham et al 2013 ).…”

Immunology of Transplant Protocols

“…Hepatocyte shedding of soluble HLA molecules may cause T cell anergy by providing a sub-threshold signal 1. Cytokines may be absorbed extensively due to the large mass of the organ, thereby exhausting the immune response, and T cell anergy may occur by clonal exhaustion due to the presence of a large load of donor antigen [38]. Finally, mixed chimerism characterized by the exchange of mesenchymal stem cells [39], dendritic cells, or hematopoietic stem cells between the donor and the allograft has been proposed as a mechanism of tolerance induction to the allograft [40 •• ].…”