In solid organ transplantation, the achievement of an immunosuppression (IS)-free state [also referred to as clinical operational tolerance (COT)] represents the ultimate goal. Although COT is feasible and safe in selected cases after liver transplantation, it is an exceptional finding after other types of solid organ transplantation. In the field of renal transplantation (RT), approximately 100 cases of COT have been reported to date, mainly in patients who were not compliant with their immunosuppressive regimens or in individuals who had previously received a bone marrow transplant for hematological disorders. On the basis of promising results obtained in animal models, several tolerogenic protocols have been attempted in humans, but most have failed to achieve robust and stable COT after RT. Molecule-based regimens have been largely ineffective, whereas cell-based regimens have provided some encouraging results. In these latter regimens, apart from standard IS, patients usually receive perioperative infusion of donor bone marrow–derived stem cells, which are able to interact with the immune cells of the host and mitigate their response to engraftment. Unfortunately, most renal transplant patients who developed acute rejection—occurring either during the weaning protocol or after complete withdrawal of IS—eventually lost their grafts. Currently, the immune monitoring necessary for predicting the presence and persistence of donor-specific unresponsiveness is not available. Overall, the present review will provide a conceptual framework for COT and conclude that stable and robust COT after RT remains an elusive goal and that the different strategies attempted to date are not yet reproducibly safe or effective.
The present review provides a conceptual framework for clinical operational tolerance (COT), and concludes that stable and robust COT after RT remains an elusive goal and that the different strategies attempted to date are not yet reproducibly safe or effective.
*Transplantation Research Immunology Group, Nuffield Department of Surgery, University of Oxford, Oxford, United Kingdom;
†Wake Forest Institute for Regenerative Medicine, Winston Salem, NC;
‡Department of Medicine, University of Wisconsin, School of Medicine and Public Health, Madison, WI;
§Department of General Surgery, Wake Forest University School of Medicine, Winston Salem, NC;
¶Department of Surgery, Division of Transplantation, University of Miami School of Medicine, Miami, FL;
‖Renal Failure and Transplant Surgery, Department of Surgery, University of L’Aquila, L’Aquila, Italy.
No funding sources have been employed.
Giuseppe Orlando, MD, PhD, is recipient of the Marie Curie International Outgoing Fellowship POIF-GA-2008-221850, financed by the European Commission under the 7th Framework Program for Research and Development. Peiman Hematti is recipient of NIH/NHLBI HL081076 K08 award.
Reprints: Giuseppe Orlando, MD, PhD, Marie Curie Fellow, University of Oxford, Nuffield Department of Surgery, Oxford, United Kingdom and Wake Forest Institute for Regenerative Medicine, Winston Salem, NC. E-mail: firstname.lastname@example.org.