Tolerance for organ recipients: A clash of paradigms

In this issue of Liver Transplantation, Donckier et al. 1 report on 3 patients with primary hepatic malignancies who underwent live donor liver transplantation. followed 1 week later by an infusion of fractionated stem cells obtained from the blood of the granulocyte colonystimulating factor (G-CSF)-conditioned donor. The intention of the Brussels team was to limit immunosuppression to the first few postoperative weeks by promptly establishing donor leukocyte chimerism-associated tolerance. In cases 1 and 2. immunosuppression was discontinued as planned, about 3 weeks postoperatively. Approximately 3 months later, mild acute rejections occurred that were reversed with a short course of immunosuppression. Treatment was then successfully stopped, with subsequent in vitro evidence of donor specific nonreactivity. These 2 patients were immunosuppression free for >95% of the time between liver replacement and death from recurrent malignancy at 561 and 356 days. For patient 3, immunosuppression discontinuance was put off until 213 days because of a surgical complication. When a reversible rejection developed. no further effort was made to stop treatment. This patient is currently on small daily doses of tacrolimus and is tumor free at 498 days. As the authors emphasized, these results were incompatible with the immunologic paradigm upon which the strategy was based. The paradigm evolved historically in the following way. After the demonstration in 1953 that acquired allotolerance is strongly associated with donor leukocyte chimerism,2 attempts were made in the 1950s to produce chimerism in cytoablated organ recipients by infusing donor leukocytes before or at the time of organ transplantation. 3 .4 Such efforts failed, because the donor cells either caused lethal graft versus host disease (GVHD) or were rejected. When human kidney transplantation was accomplished in the early 1960s under continuous drug immunosuppression without cytoablation/reduction or leukocyte infusion, it was widely concluded that leukocyte chimerism played no role in the induction or the perpetuation of organ alloengraftment. 5 With this assumption, experimental efforts were renewed to give organ reCipients the tolerance advantages of leukocyte chimerism while avoiding GVHD. This proved to be possible in selected cytoablation and cytoreduction models.6 B but only when donor cells made up 2: 1 % of the recipient blood leukocytes (macrochimerism).9 Lower levels (micro chimerism) had no effect. When these model-specific observations were generalized, the sharp distinction between macro chimerism and microchimerism became dogma. 10-13 In addition, the dogma that organ engraftment occurs by mechanisms different from bone marrow transplantation appeared to be strengthened. The foregoing dogmas, as well as the overarching immunologic paradigm that had been distorted by the incorporation of those dogmas, were challenged in 1991-92, when multilineage donor leukocyte microchimerism was detected in all long-surviving human organ recipients. 14.15 It was evident that migration of an organ's passenger leukocytes (including stem cells) into the reCipient had been the previously unrecognized equivalent of a bone marrow cell infusion. The picture was made complete by the demonstration of "reversed proportion" mixed chimerism (i.e .. small numbers of persisting host leukocytes) in essentially all bone marrow recipients previously thought to have total hematolymphopoietic cell replacement. 16 These findings unified the immunology of the 2 kinds of transplantation. 1 7