Minimal But Essential Doses of Immunosuppression: A More Realistic Approach to Improve Long-Term Outcomes for Pediatric Living-Donor Liver Transplantation

The majority of transplant (Tx) patients remain dependent on the chronic administration of immunosuppression (IS) regardless of its associated complications. Tolerance (long-term acceptance of a transplanted organ after the complete cessation of IS) is the ultimate goal. No less than 15% of all pediatric patients who underwent living-donor liver Tx in Kyoto were weaned off IS. Such cases are referred as showing “operational tolerance” in the absence of any histologic definition (1). Currently, two distinct types of mechanism are documented in tolerance: (a) deletional mechanisms in which T cells potentially reactive to donor antigens are eliminated from the immune repertoire and (b) nondeletional mechanisms in which such T cells are physically present, but inhibited by certain mechanisms. Immunologic analyses of our IS-free patients demonstrated that regulatory T cells (Tregs) would be likely to suppress the existing reactive T cells through intragraft Th2 cytokine immune deviation, and, thereby, nondeletional mechanisms play a determinant role in operational tolerance (2–5). We performed protocol biopsy on IS-free patients to examine whether accepted grafts exhibit a normal histology. Approximately 50% of IS-free patients, albeit showing a normal liver test, exhibited graft fibrosis to a greater extent than those on maintenance IS (6). For fear of the progression of fibrosis, we reintroduced minimal maintenance immunosuppression (MMIS) for IS-free patients or patients who exhibited fibrosis during the process of weaning IS. Follow-up biopsy was performed after the reintroduction of MMIS to examine how MMIS effects on fibrosis. In most patients, fibrosis did not progress. In 52% of them, fibrosis was improved, and in 38% of them, it did not change. It is debatable whether graft fibrosis observed in stable pediatric liver Tx recipients can be prevented by MMIS. One IS-free patient did not start MMIS despite the presence of fibrosis (6). This patient exhibits rapid progression of fibrosis within a year, which was not observed in patients who started MMIS. Our results suggest that, at least in part, fibrosis can be prevented by MMIS. Therefore, this implies that, in accordance with the recommendation of The Banff Working Group, operational tolerance necessitates Working Histopathologic Criteria (A. Demetris, personal communication Banff '09, Banff, Alberta, Canada, August 9–14, 2009). Of course, one must be cautious as to whether one biopsy sample would always represent the overall condition of grafts, especially in partial liver Tx. When the sample is obtained from the area near the cut surface, nonimmunologic surgical effects can affect the histologic findings. Nondeletional mechanisms mediated by Tregs may not always be sufficient to control low-grade destructive immune responses. Alternatively, specific cytokines (e.g., transforming growth factor-β), which are produced by Tregs, may be responsible for fibrosis, as recently discussed by Magee (7). The other possibility is that operational tolerance associated with both a Treg-mediated mechanism and intragraft Th2 immune deviation, albeit important for the establishment of in vivo hyporesponsiveness and protection against acute rejection, may correlate with the development of antibody-mediated rejection by promoting humoral responses, as shown by our experiment (8). In fact, our preliminary study demonstrated the deposition of C4d within the graft in some IS-free patients, but such deposition was decreased or disappeared in cases where MMIS was effective in improving fibrosis (H. Egawa, personal communication, 14th European Society for Organ Transplantation Congress, Paris, France, August 30 to September 2, 2009). It may well be that true tolerance requires more robust deletional mechanisms, notably through the creation of mixed chimerism, which has been successfully established in renal Tx by the Boston group (T. Kawai, personal communication, XXIII International Congress of TTS, Vancouver, Canada August 15–19, 2010). In this letter, we propose the following guidelines for the management of patients in whom graft fibrosis is observed using protocol biopsy after stopping IS or during the process of weaning IS, based on our experiences of MMIS in patients with graft fibrosis (Table 1).TABLE 1: The reintroduction of minimal maintenance immunosuppression Criteria for the reintroduction of MMIS: Advanced fibrosis (Ishak's modified staging ≥3, focal moderate perivenular fibrosis (>30-μm thickness)). Progression of fibrosis. MMIS: 0.01 to 0.04 mg/kg of tacrolimus monotherapy once a day. Close follow-up by protocol biopsy every 6 to 12 months. In conclusion, although the complete cessation of IS represents the ultimate goal, use of minimal but essential doses of IS can be a more realistic approach in some patients in whom the complete cessation of IS has been attempted. This is in accordance with the concept first described by Calne et al. (9). ACKNOWLEDGMENTS The authors thank Drs. E. Kobayashi, J. Pirenne, and A. Demetris for their helpful discussions and the critical reading of this article, and Dr. Parker and Ms. Nakanishi for manuscript preparation. Hidenori Ohe1 Ying Li2 Hanaa Nafady-Hego1 Waki Kayo3 Shimon Sakaguchi2 Kathryn Wood4 Roy Calne5 Shinji Uemoto1 Takaaki Koshiba1 1 Department of Surgery Graduate School of Medicine Kyoto University Kyoto, Japan 2 Department of Experimental Pathology Institute for Frontier Medical Science Kyoto University Kyoto, Japan 3 Department of Ubiquitous Health Informatics Graduate school of Medicine The University of Tokyo Tokyo, Japan 4 Transplantation Research Immunology Group Nuffield Department of Surgery University of Oxford John Radcliffe Hospital Headington, Oxford, United Kingdom 5 Department of Surgery & Medicine University of Cambridge United Kingdom and National University of Singapore, Singapore

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