Finding the right time for weaning off immunosuppression in solid organ transplant recipients

Solid organ transplantation (SOT) requires lifelong immunosuppression (IS) to prevent rejection and graft loss The currently adopted immunosuppressive protocols are numerous and are based on the administration of at least two molecules with diverse mechanisms of action Owing to the fact that the majority of immunosuppressants act non-selectively the immune system is normally oversuppressed and as a result is less able to both defend the host against infection and to control the spread of malignant cells Consequently long-term IS is burdened by chronic toxicity which may be highly invalidating and may significantly influence patient s quality of life compliance to treatment overall success rate and patient and graft survival In an ideal scenario SOT recipients should initially receive just enough IS to favor the onset of clinical operational tolerance (COT), a condition where the immune system of the host does not attack the graft in the absence of any immunosuppressant COT has been documented after liver transplantation (LT) and renal transplantation (RT) First COT was accidentally detected in patients who were nonadherent to treatment and who spontaneously decided to stop all IS without any medical guidance or surveillance Later it was described in recipients who required IS withdrawal following the occurrence of malignant diseases Based on strikingly convincing experimental data several tolerogenic protocols have recently been applied in patients but overall the results have been disappointing The current literature demonstrates that COT can be safely achieved in stable LT recipients with completely different strategies Importantly the onset of an episode of acute rejection during the attempt of IS withdrawal would not worsen the clinical outcome On the contrary COT remains a major challenge after RT because the onset of acute rejection will substantiate in graft loss Currently a major field of investigation aims to define markers of COT which will allow the selection of individuals who are more prone to develop COT Preliminary results in both RT and LT have just been announced however these markers will require validation in prospective studies