Delayed low-level calcineurin inhibition promotes allospecific tolerance induction by posttransplantation donor leukocyte infusion1

Abstract

Postoperative donor leukocyte infusion is a potential way for tolerance induction, but the type, dose, and timing of medication are highly critical for its efficacy.

A short course of cyclosporine immunosuppression inhibits rejection but not tolerance of rat liver allografts1

“…Our results for delay of CsA administration support this possibility, which has been previously proposed as a "window of opportunity for immunologic engagement" (38). They are also in full agreement with findings in a rat heart transplant model in which, in combination with infusion of donor splenocytes, administration of CsA from days 6 to 10 induced long-term survival, whereas administration from days 0 to 4 did not prolong survival (39). The outcome for delayed CsA treatment in rat liver transplantation is also in agreement with the finding that delay of MP immunosuppression leads to longer survival of rat liver transplants in a rejecting strain combination (8).…”

Role of the Hepatic Parenchyma in Liver Transplant Tolerance: A Paradigm Revisited

“…Infusion of donor leukocytes at the time of transplantation (to mimic PLs migrating out of the graft) has been used in several mouse and rat transplant models to prolong graft survival [59,60]. These studies recapitulate the ability of donor PBMC to induce tolerance (the so-called ‘blood transfusion effect’ [61]) and have demonstrated some (sometimes limited) success in extending graft survival.…”

A short course of mycophenolate immunosuppression inhibits rejection, but not tolerance, of rat liver allografts in association with inhibition of interleukin-4 and alloantibody responses

“…It shows that MMF does not inhibit tolerance, although it does prevent rejection. In contrast with methylprednisolone (6) and CsA (24), in which delay of administration increases their effectiveness in preventing rejection, delay of MMF immunosuppression reduced its effectiveness. This study is the first to examine the effect of MMF on a model of spontaneous transplant acceptance and does not provide evidence that it inhibits acceptance, although there was a nonsignificant increase in the number of deaths of MMF-treated TOL animals because of an increase in biliary complications.…”

“…Piebald Virol Glaxo (PVG) strain liver allografts are spontaneously accepted without immunosuppression in major histocompatibility complex-mismatched Dark Agouti (DA) strain recipients and rapidly induce tolerance (TOL) to donor-strain skin grafts, whereas PVG livers transplanted into Lewis (LEW) recipients are rapidly rejected (REJ) (22,23). Because tolerance-associated immune activation occurs early after transplantation, delay of immunosuppression might therefore improve its effectiveness, as has been demonstrated (6,24). The effect of delay of MMF administration on liver transplant acceptance and rejection and on the pattern of infiltration, cytokine gene expression, and immunoglobulin (Ig) deposition was also examined.…”