The rationale for this trial was based in part on the previous observation in early 1992 that 15% of our liver recipients followed >10 years had discontinued all medications 5 to 13 years previously without developing rejection (1
). With 2½ more years of follow-up, these 6 recipients, who for the most part had reached a drug-free status by noncompliance, are still well with 2½ more years follow-up. A further collection of 5 children whose physician-directed drug discontinuance .5 to 8 years posttransplantation was prompted by the development of Epstein-Barr–associated B cell lymphomas (4
) continue to be stable and now have been drug-free for from 1 or to 3.3 years.
The prospective weaning trial herein reported has confirmed our suspicion that many long-term survivors after liver transplantation no longer need chronic immunosuppression at the prescribed levels, if at all. One-fourth of the patients entered have been able to discontinue immunosuppression altogether, half are still weaning without complications, and only a quarter have failed the effort. No hepatic grafts have been lost and none has suffered measurable damage. The only significant complication was in a patient who developed readily treated herpes keratitis. In 2 examples of histopathologically severe rejection, a safety net was provided by the “rescue” capabilities of FK506 (8
) to which the patients were converted.
The need for close and continuance medical surveillance was evident. All of the rejections were signaled without the occurrence of jaundice by rises in the transaminase levels and in the canalicular tests of which the GGTP is the most specific. Confirmatory allograft biopsies were of the utmost importance for management decisions because enzyme rises during weaning were seen with equal frequency in allografts with and without evidence of rejection. There was no clear explanation for the transient enzyme increases in patients whose weaning was not interrupted. One possibility was that there was an unapparent and self-resolving rejection. Another might have been the loss during drug withdrawal of the hepatotrophic effects of either cyclosporine (9
) or FK506 (10
). Two of these nonrejecting patients have had waxing and waning of the enzyme activity during further weaning or drug stoppage.
Although it is too soon to be confident about the safety of the weaned patients, the demonstration of allograft stability in the previously reported drug-free patients for as long as 15 years is reassuring. In the presently reported prospective study, the peak risk appeared to have been passed by the sixth month. Early dividends of discontinuance of immunosuppression have already been seen, most frequently the involution of benign as well as malignant skin lesions. Disappointingly, there has been no improvement in preexisting arterial hypertension or renal dysfunction.
The subgroup of 13 patients with previously documented chimerism was of special interest. We have emphasized frequently our belief that this chimerism is a cardinal requirement for allograft acceptance and for the potential eventual evolution of donor specific nonreactivity (tolerance) but that it is not synonymous with either outcome. The proposition as originally stated was that “Clinical success—tolerance or graft acceptance—means that a characteristic lymphoid and dendritic cell chimerism has been introduced, which may be stable either without further treatment or only when continued immunosuppression is provided; an unstable graft and its migrated cells may either be rejected or cause GVHD” (2
). The heterogeneity of results from weaning in these 13 cases conformed entirely with this central hypothesis. Although 9 of the 13 liver recipients have been able to stop drugs (n=7) or are successfully weaning (n=2), the onset of rejection required resumption of immunosuppression in the other 4.
As discussed in detail elsewhere (11
), acceptance of whole-organ allografts and the achievement of a drug-free state are in fact mirror image events to those occurring after successful bone marrow transplantation in cytoablated recipients. The fundamental difference is that the trace leukocyte population in the David/Goliath cell relationship following whole-organ transplantation is donor rather than recipient, with the obvious implication that the principal risk is rejection rather than GVHD. Using this two-way paradigm of transplantation immunology, it is easy to understand the lengthy periods of immunosuppressive coverage that are usually necessary before a drug-free state can evolve. When bone marrow transplantation is from MHC-matched donors, continuous immunosuppression is frequently required for a year or more, and when there are 1 to 3 HLA allele mismatches, a period of 5 years or longer is needed before drugs can be stopped.
The liver transplant recipient has delineated an even more protracted time frame for solid-organ recipients of mismatched whole-cadaver organs (12
). The risk in liver recipients of weaning attempts too early, too abruptly, or without frequent testing of allograft function have been described by Sanborn et al. (13
) in a series of patients weaned from a cyclosporine-based triple-drug therapy. Moderate-to-severe rejection was frequently encountered in this series of 12 cases, leading to secondary complications after renewal of high-dose immunosuppression and eventually 2 deaths. The difficulty of weaning from cyclosporine when it was part of a triple-drug regimen also was noted in our experience.
Although this study was concerned only with liver allografts, we believe that the same trends can be found with other whole organs if these are systematically looked for. Five of our long-term recipients of living-related kidneys (not twins) have been off of immunosuppression for 1, 1.7, 14, 28, and 29 years (3
). However, the lower density of chimerism in kidney and heart recipients undoubtedly makes weaning more hazardous than in the recipient of the inherently tolerant liver, and consequently this has been attempted only when there are immunosuppression-associated life-threatening complications (14
The inability to accurately predict which patients can be successfully weaned means that all such attempts are on a trial-and-error basis, particularly when the donor leukocytes are unavailable for prognostic in vitro testing. Because we did not have donor lymphoid tissue in any of the liver weaning cases, we attempted to test recipient responsiveness to cells homozygous to the donor DR antigens as described by Reinsmoen et al. (6
). A trend was noted of antidonor responsiveness in the rejection group and nonresponsiveness in patients successfully weaned, but this was imprecise. It has been pointed out before that even in vitro testing with donor cells does not correlate well with tolerance in animals (15
) and humans (18
). This fundamental limitation of in vitro testing, rather than inherent imperfections in the surrogate technique of homozygous typing, shows that more predictive methods need to be developed.