Abstract
The induction of specific tolerance, in order to avoid the detrimental effects of lifelong systemic immunosuppressive therapy after organ transplantation, has been considered the “Holy Grail” of transplantation. Experimentally, tolerance has been achieved through clonal deletion, through costimulatory blockade, through the induction or infusion of regulatory T-cells, and through the establishment of hematopoietic chimerism following donor bone marrow transplantation. The focus of this review is how tolerance has been achieved following combined bone marrow and kidney transplantation. Preclinical models of combined bone marrow and kidney transplantation have shown that tolerance can be achieved through either transient or sustained hematopoietic chimerism. Combined transplants for patients with multiple myeloma have shown that organ tolerance and prolonged disease remissions can be accomplished with such an approach. Similarly, multiple clinical strategies for achieving tolerance in patients without an underlying malignancy have been described, in the context of either transient or durable mixed chimerism or sustained full donor hematopoiesis. To expand the chimerism approach to deceased donor transplants, a delayed tolerance approach, which will involve organ transplantation with conventional immunosuppression followed months later by bone marrow transplantation, has been successful in a primate model. As combined bone marrow and organ transplantation become safer and increasingly successful, the achievement of specific tolerance may become more widely applicable.
Highlights
The “Holy Grail” of solid organ transplantation is the induction of donor specific immunological tolerance in order to avoid the complications of long-term systemic immunosuppressive therapy
Lifelong tolerance of full thickness skin allografts across major histocompatibility barriers following nonmyeloablative conditioning and donor bone marrow with the induction of durable chimerism was demonstrated by Slavin and colleagues, who showed that tolerance of organ allografts could be accomplished without the requirement of sustained chimerism [22, 23]
Sustained mixed lymphohematopoietic chimerism was demonstrated after “mixed marrow transplantation” involving the infusion of T-cell depleted autologous and allogeneic marrow following myeloablative conditioning in murine and miniature swine models which resulted in a tolerance of donor skin allografts [24, 25]
Summary
The “Holy Grail” of solid organ transplantation is the induction of donor specific immunological tolerance in order to avoid the complications of long-term systemic immunosuppressive therapy. A minority of patients who have stopped their systemic immunosuppressive therapy (usually on their own) have subsequently had normal allograft function This socalled spontaneous tolerance has been reported in up to 20% of liver transplant recipients, but only rarely in recipients of a kidney transplant [11, 12]. There are numerous anecdotes of patients who received a kidney transplant after a prior hematopoietic cell transplant for a hematologic malignancy or other life-threatening blood disorder from the same donor [13] These recipients have expectedly accepted the kidney allograft without systemic immunosuppression. The focus of this review will be the induction of specific tolerance through hematopoietic chimerism following combined bone marrow and kidney transplantation. Haploidentical/mismatched related and unrelated donor KdBMT for ESRD without malignancy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
