Tolerance in clinical transplantation: progress, challenge or just a dream?

The achievement of clinical operational tolerance (COT) is still considered a major goal in the academic field of solid organ transplantation. Even COT is feasible and safe in selected cases after liver transplantation, in the clinical arena of solid organ transplantation, tolerance remains, for the most part, a concept rather than a reality.

Although modern immunosuppression regimens have effectively handled acute rejection, nearly all organs except the liver commonly suffer chronic immunologic damage that impairs organ function, threatening patient and allograft survival. Strong arguments in favour of conducting clinical tolerance trials are the high number of grafts still lost due to chronic rejection, the burden of serious adverse effects from immunosuppressants which causes considerable cardiovascular morbidity and mortality, respectively, and the fact that sporadic tolerance can be observed in rare cases where non-adherence to immunosuppressive regimens is linked with a state of long-lasting organ tolerance. Whereas molecule-based regimens have been largely ineffective, cell-based tolerance protocols have delivered some encouraging results to achieve COT.

In combination with donor bone marrow-derived stem cells, some encouraging results in COT development were reported lately for renal transplantation as well. However, less toxic conditioning protocols and more experience by use of cell products with regulatory properties in combination with synergizing immunosuppressive drugs is required to launch future tolerance trials for a broader spectrum of potential transplant candidates. New methods in immunomonitoring including biomarkers, microarray-based genetic tolerance signatures and functional assays may pave the way to achieve COT in upcoming clinical trials.