Short-term results following organ transplantation have been significantly improved by the use of increasingly efficacious immunosuppressive agents. However, their chronic use results in significant morbidity, especially from an increased incidence of cardiovascular disease, infection, malignancies, de novo diabetes and other metabolic derangements. Additionally, the potent immunomodulatory effects of current therapeutic protocols do not prevent the development of chronic rejection, despite their administration being pushed to toxic levels. Therefore, induction of tolerance, defined as the absence of destructive immune responses to a transplanted tissue without ongoing immunosuppressive therapy, remains the ultimate goal of organ transplantation.

Since the seminal work reported by Billingham, Brent and Medawar on neonatal tolerance in 1956, numerous tolerance induction strategies have been identified in rodents. However, only a very limited number of these have been successfully translated to large animals and even fewer to primates. Among the few protocols that have been applied in humans, induction of donor chimerism, either transient or permanent, currently appears to be the most promising strategy to achieve renal allograft tolerance. Initial results of clinical trials for tolerance induction in three centers have so far been reported.

Using TLI and DBMT, the Stanford group has reported successful induction of stable chimerism and renal allograft tolerance in HLA identical kidney transplant recipients. Extension of this approach to recipients of HLA-mismatched renal allografts has not yet been reported. More recently, the Northwestern group has reported the use of a Fludarabine-based conditioning regimen, donor hematopoietic stem cells, and a unique “Facilitator Cell” for induction of tolerance in HLA-mismatched kidney transplant recipients. Although the follow-up is still brief, persistent donor chimerism without GVHD has been reported, allowing weaning from all maintenance immunosuppression in approximately half of their patients.

At Massachusetts General Hospital, based on decades-long basic studies in animal models, we have applied combined kidney and donor bone marrow transplantation (CKBMT) for induction of allograft tolerance in both HLA matched and mismatched kidney transplant recipients. Ten patients with renal failure secondary to multiple myeloma have been treated with CKBMT from HLA-matched siblings, following a nonmyeloablative preparative regimen consisting of cyclophosphamide, local thymic irradiation, ATG and a brief course of post transplant cyclosporine. All recipients developed mixed chimerism and renal allograft tolerance. Two patients have died, of recurrent myeloma, 4 and 8 years after CKBMT. The remaining 8 are alive with normal allograft function with F/U periods of up to 14 years.

Following similar conditioning, CKBMT has been performed in 10 recipients of HLA-mismatched kidney allografts. Stable renal function without immunosuppression has been achieved for periods of 2.6 – 9 years in seven of these recipients. The protocol is currently being modified in non-human primates in order to extend it to recipients of deceased donor allografts.

In conclusion, observations from three clinical trials, utilizing the mixed chimerism approach to tolerance induction, emphasize that the consistent induction of tolerance in human allograft recipients may finally be achievable.