Clinical Operational Tolerance After Renal Transplantation

Abstract

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.

Tolerance--Is It Worth It?

“…Similar findings have been found in renal transplants with operational tolerance after total lymphoid irradiation (Strober et al 1989(Strober et al , 2000. A number of case reports have documented spontaneous tolerance in a subset of patients undergoing immunosuppression withdrawal for treatment of PTLD (Orlando et al 2010). …”

“…There have been many reports of sporadic tolerance identified in noncompliant patients (summarized by Orlando et al 2010). It is clear that organs differ in their response to cessation of immunosuppression out of noncompliance.…”

“…It is clear that organs differ in their response to cessation of immunosuppression out of noncompliance. There have been many reports of tolerance in kidney transplantation (Orlando et al 2010), a single report in lung transplant (Di Cocco et al 2009), and no reports in pancreas transplant. Liver transplant recipients are most likely to have continued graft function after cessation of immunosuppression.…”

“…These approaches can be divided into three main groups: (1) study of noncompliant patients that show spontaneous tolerance following discontinuation of immunosuppression, (2) patients with stable long-term graft function that undergo planned immunosuppression minimization and cessation, and (3) pretransplant-planned protocols for tolerance induction via pharmacologic or cellular therapy (Orlando et al 2010). There are examples of successful withdrawal of immunosuppression with each of these approaches.…”

“…This may be defined as "a well-functioning graft lacking histological signs of rejection, in the absence of any immunosuppressive drugs (for at least 1 year), in an immunocompetent host" Orlando et al 2010). Operational tolerance may further be clarified to include the absence of antibody-mediated rejection.…”