More than half a century ago, Billingham and Medawar described the phenomenon of acquired immunologic tolerance to transplant antigens by successfully grafting the skin of a calf onto its fraternal twin. Induction of immune tolerance decreases the risk of graft rejection after solid organ transplantation and thus reduces the need for immunosuppression and improves the survival of transplanted organs. Billingham’s work was followed by the first successful kidney transplant in 1954, and so launched the worldwide search for methods to induce immune tolerance and to hold graft rejection at bay. Transplant tolerance represents the holy grail for transplant immunology: a state where the allograft is accepted by the recipient in the absence of IS treatment. There are multiple types of tolerance including full immunological tolerance, operational tolerance (OT), or IS minimization, sometimes referred to as “prope tolerance”.

Transplantation of organs, including the liver, across the HLA barrier induces strong alloimmune responses in recipients. Both cellular and humoral alloresponses contribute to rejection. More than half a century ago, Billingham and Medawar described the phenomenon of acquired immunologic tolerance to transplant antigens by successfully grafting the skin of a calf onto its fraternal twin. Induction of immune tolerance decreases the risk of graft rejection after solid organ transplantation and thus reduces the need for immunosuppression and improves the survival of transplanted organs. Billingham’s work was followed by the first successful kidney transplant in 1954, and so launched the worldwide search for methods to induce immune tolerance and to hold graft rejection at bay. Transplant tolerance represents the holy grail for transplant immunology: a state where the allograft is accepted by the recipient in the absence of IS treatment. There are multiple types of tolerance including full immunological tolerance, operational tolerance (OT), or IS minimization, sometimes referred to as “prope tolerance”. In the practical setting, research is focused on the induction of OT, which is defined as stable graft function in the absence of IS for more than one year without any features of chronic rejection. Efforts to develop OT have capitalized on how the immune system actively regulates itself through regulatory T cells, B cells, and innate components. Studied methods for developing OT include hematopoietic stem cell transplantation that re-educates the immune system and targeted stimulation by transfer of immune regulatory cells. Antigen-presenting cells (APCs), Kupffer cells (KCs), non-immune cells such as mesenchymal cells (MSCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs) have regulatory properties as well . The use of cells as therapeutics, particularly regulatory T cells (Tregs), regulatory dendritic cells (DCregs), and MSCs have attracted enthusiasm as alternative OT induction strategies in transplants.