Transplantation tolerance: Coming of age
Authors: Andrew B. Adams, Kenneth A. Newell
Journal: Hepatology (2016)

Potential conflict of interest: Dr. Newell consults and is on the speakers' bureau for Novartis. He also consults for Immucor and Merck. See Article on Page 632 Even before Medawar and colleagues published their seminal description of long‐term skin transplant survival in mice in the early 1950s, the field of transplantation was fascinated by the concept of tolerance.1 Following this pioneering work, many thought that clinical tolerance was just around the corner. However, the first report of clinical tolerance was not published until 1975.2 It took another 10‐20 years before advances in immunology suggested approaches that could be exploited to induce tolerance in humans. These advances included protocols in rodents that induced a state of mixed hematopoietic chimerism and subsequent tolerance to transplanted organs and the description of T cells with suppressive or regulatory properties.3 In this issue of Hepatology, Todo et al.6 report 10 patients undergoing living donor liver transplantation who received an infusion of an ex vivo‐generated cell product enriched for regulatory cells with the aim of inducing tolerance. Tapering of immunosuppression began at 6 months, with complete withdrawal achieved by 18 months. This was successful in 7 of the 10 patients, with the three failures occurring in individuals with autoimmune liver diseases. At the time of this report, the duration of tolerance ranged from 16 to 33 months. Importantly, the cell infusion was not associated with any adverse events, and all treated patients—including the 3 who failed weaning of immunosuppressive drugs—have normal graft function without histologic evidence of injury. So why is the Todo et al. study significant? Despite over two decades of work aimed at characterizing regulatory cells, determining how they mediate their suppressive effects, and developing protocols to expand them, this study is the first to demonstrate that they can be exploited to induce tolerance after organ transplantation. This is also the first study to intentionally induce tolerance in patients undergoing liver transplantation. How does this work compare with and advance previous studies of tolerance in liver transplant recipients? Previous studies have capitalized on the relatively high incidence of spontaneous tolerance after liver transplantation to permit the gradual withdrawal of immunosuppression in liver transplant recipients initially treated with conventional immunosuppressive regimens. These studies have found that the success of weaning recipients from immunosuppressive drugs was strongly correlated with increasing time since transplantation.7 The advantage of the approach described by Todo et al. is that it allows for earlier withdrawal of the drugs, thereby saving patients years of the morbidities associated with immunosuppression. Several groups have reported strategies that induce tolerance to transplanted kidneys with significant success. Each of these protocols use the infusion of various populations of donor cells in the setting of recipient conditioning consisting of irradiation and non‐myeloablative chemotherapeutic agents to induce variable states of chimerism.8 It remains to be determined whether these differences between the strategies for inducing tolerance following liver and kidney transplantation reflect fundamental organ‐specific differences in the mechanisms responsible for the development and maintenance of tolerance or are artifacts related to differences in the patient populations studied, study design, and the choices of the relatively small number of investigative teams. However, should regulatory‐based therapies prove equally effective in each setting, it is worth noting that regulatory T cell (Treg)‐based strategies may offer the theoretical advantages of inducing tolerance without exposing recipients to the potential long‐term consequences associated with irradiation and exposure to chemotherapeutic agents. In the final analysis, where does the report by Todo et al. fit in the evolution of advances that are bringing the field ever closer to realizing the dream of tolerance? As shown in Fig. 1, this study is but one step in a long journey to tolerance. Although the current study is certainly a significant advance, it would be imprudent to conclude that tolerance has finally come of age and will be broadly available in the near future. For years, the work of Medawar and colleagues was misinterpreted as demonstrating that a brief intervention could induce permanent tolerance in the vast majority of recipients, when in fact the investigators themselves concluded that tolerance represented a spectrum rather than an "all or none" phenomenon, that it was not necessarily permanent, that immunologic memory could overcome or prevent its development, and that it could not be achieved in all individuals.Figure 1: Milestones in transplantation tolerance.So what are the challenges for the future? First, it would seem important to better understand the biology of adoptively transferred regulatory cells. Where do they migrate, how long do they survive, and how do they mediate their suppressive effects on alloimmunity? It seems highly unlikely that they perpetually expand and survive for the life of the recipient. If this is the case, what mechanisms emerge to maintain the tolerogenic state induced by transfer of regulatory cells as they disappear? Understanding the answers to these questions may allow current strategies to be optimized to overcome some of the barriers that currently prevent the broader application of Treg‐based approaches to tolerance. For example, in the current study transfer of Tregs into recipients with autoimmune liver diseases failed to result in tolerance. Trials of induced tolerance in kidney transplant recipients have generally been most successful in partially matched donor‐recipient pairs and those with lower levels of sensitization. Can we optimize the current strategies to benefit these populations, or will new approaches be needed? More specifically, to date, logistic considerations have prevented the field from developing strategies that can be used in the setting of deceased organ donation, thereby excluding the majority of transplant recipients. Perhaps most importantly, we need to guard against accepting on faith that the current approaches to inducing tolerance will provide dramatically improved outcomes in comparison with optimized regimens of immunosuppressive agents. Although logic dictates that avoiding the well‐recognized toxicities and morbidities associated immunosuppressive agents would improve both quality of life and survival following transplantation, the field should continue to require that each new approach to controlling alloimmunity after transplantation be formally evaluated in the same types of prospective, controlled, multicenter studies that have allowed the development of the regimens that have advanced the field so significantly in recent decades. The good news in this respect is that the field is currently in the midst of a period of rapid development. Several collaborative groups—including the Clinical Trials in Organ Transplantation and the Clinical Trials in Organ Transplantation in Children consortia, the Immune Tolerance Network, and the ONE Study—are conducting clinical trials to develop and optimize the therapeutic use of regulatory cells in transplantation. Given this focus, perhaps it is realistic to believe that robust, broadly applicable Treg‐based regimens in transplantation are on the horizon. Author names in bold indicated shared co‐first authorship.