Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation

In the setting of our pediatric living-donor liver transplantation (LDLT), 87 patients (15.0% of all the patients: significantly higher proportion, compared with those of other transplant centers) achieved complete withdrawal of immunosuppression, which is referred to as "operational tolerance". Immunosuppressants were completely discontinued for 54 patients as scheduled, and for 33 because of EBV infection or other complications. Immunological analyses of the peripheral blood derived from operationally tolerant patients demonstrated that non-deletional tolerance takes place in which potentially reactive T cells to donor-antigens remain physically in the immune repertoire, but specifically suppressed by certain mechanisms. Not only CD4(+)CD25(high+) T cells were increased in the proportion in the tolerant patients' peripheral lymphocytes and suppressed MLR specifically to the donor antigen, but also FOXP3 expressing cells were present within the tolerant liver. Thus, among several mechanisms accounting for non-deletional tolerance, Tregs are likely to involve at least in part in our tolerant patients. V delta 1 gamma delta T cells, a subset of gamma delta T cells, which otherwise reside mainly in the intestine, emerge into the peripheral blood during successful pregnancy but not abortive pregnancy. Since V delta 1 gamma delta T cells produce massive IL-10, it is proposed that V delta 1 gamma delta T cells induce fetomatemal tolerance by promoting Th2 immune deviation. Consistent with pregnancy, IL-10 producing V delta 1 gamma delta T cells emerge into the blood of our tolerant patients. This may reflect a common feature between fetomatemal tolerance and transplant tolerance. We began protocol biopsy in post-LDLT patients who exhibit normal liver function from January 2003. Operationally tolerant patients, albeit showing normal liver function, exhibited decrease in size and increase in number of the bile duct and the fibrosis to a greater extent, compared with patients on maintenance immunosuppression. This warrants serial protocol biopsy before and after complete cessation of immunosuppression even in the presence of normal liver function. (c) 2006 Elsevier B.V. All rights reserved.